Triazolopyridine compounds and their use as ask inhibitors

ABSTRACT

The present invention relates to triazolopyridine compounds according to Formula (I), their use as medicament, for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and/or neurodegenerative diseases and a process for their preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/666,445, filed Dec. 23, 2009, which is the U.S. national stageapplication of International Patent Application No. PCT/EP2008/060884,filed Aug. 20, 2008, which claims the benefit of U.S. Provisional PatentApplication No. 60/966,989, filed Aug. 31, 2007, the disclosures ofwhich are hereby incorporated by reference in their entirety, includingall figures, tables and amino acid or nucleic acid sequences.

FIELD OF THE INVENTION

The present invention relates to triazolopyridine compounds according toFormula (I), their use as medicament, for treating autoimmune disorders,inflammatory diseases, cardiovascular diseases and/or neurodegenerativediseases and a process for their preparation.

BACKGROUND OF THE INVENTION

ASK (apoptosis signal-regulating kinase) has been described as amitogen-activated protein kinase. ASK-1 and ASK-2 have been described asmembers of the ASK family. ASK-1 is a MAPKKK (mitogen-activated proteinkinase kinase kinase). Human and mouse ASK-1 consist of 1374 and 1380amino acids, respectively, and possess a serine/threonine kinase domain.ASK-1 is activated by environmental stress. The stimuli include interalia H₂O₂, LPS, ROS (reactive oxygen species), ER stress, influx ofcalcium ions, and various cytokines such as TNF (tumor necrosis factor)have been described to be stimuli. ASK-1 in turn induces various stressresponses including apoptosis and has been described to mediate variouscellular responses including survival and differentiation. ASK-1 is amember of the MAPKKK family that constitutes the JNK and p38 MAP kinase(MAPK) cascades. Trx (thioredoxin) was identified as a repressor ofASK-1 and also forms part of the “ASK-1 signalosome”, a high molecularmass complex. ASK has been described to be involved in various diseasesassociated with autoimmune disorders and neurodegenerative disorders(e.g. H. Nagai et al., J. Biochem. and Mol. Biol., Vol. 40, No. 1,January 2007, pp. 1-6).

SUMMARY OF THE INVENTION

According to one aspect of the invention, are provided triazolopyridinecompounds according to Formula (I):

-   -   wherein    -   R₁ is selected from    -   a. hydrogen;    -   b. C₁-C₆-alkyl;    -   c. C₂-C₆-alkenyl optionally substituted with C₁-C₆-alkyl;    -   d. —NR₆R₇;    -   e. C₃-C₈-cycloalkoxy, C₁-C₆-alkoxy;    -   f. C₃-C₈-cycloalkyl sulfanyl, C₁-C₆-alkyl sulfanyl; and    -   g. 5 or 6-membered heteroaryl having at least one heteroatom        selected from N, S and O, said heteroaryl being optionally        substituted with C₁-C₆ alkyl, halogen, or C₁-C₆ alkoxy;    -   R₂ is selected from    -   a. hydrogen;    -   b. halogen;    -   c. aryl optionally substituted with R₁₀, R₁₁ and/or R₁₂; and    -   d. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N, S and O and optionally substituted with C₁-C₆        alkyl;    -   or R₁ and R₂ taken together form a —C═C—C═C— group-;    -   R₃ is selected from    -   a. hydrogen;    -   b. halogen; and    -   c. C₁-C₆-alkyl optionally substituted with at least one fluoro;    -   R₄ is selected from    -   a. hydrogen; and    -   b. 5 or 6-membered heteroaryl having at least one heteroatom        selected from N, S and O;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NC(O)R′ wherein R′ is aryl optionally substituted with            C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆-cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxy carbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NHC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy,        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O,        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N, O or S optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl,        -   iii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl or —N(C₁-C₆-alkyl)₂, wherein the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or hydroxy;        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;        -   vii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N optionally substituted with            hydroxy, —C(O)OR′ wherein R′ is C₁-C₆-alkyl, halogen or            C₁-C₆-alkyl;        -   viii. amino;        -   ix. —NH(amino-C₁-C₆-alkyl);        -   x. —N(C₁-C₆-alkyl)₂;    -   R₆ is selected from    -   a. C₁-C₆-alkyl optionally substituted with one or two hydroxy        groups,    -   b. phenyl optionally substituted with at least one of the        following groups        -   i. halogen        -   ii. C₁-C₆-alkyl, or        -   iii. C₁-C₆-alkoxy;    -   c. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from O and N optionally substituted with C₁-C₆-alkyl;    -   d. C₃-C₈-cycloalkyl optionally substituted with R₈; and    -   e. —(CH₂)_(n)R₉ wherein n equals 1, 2 or 3;    -   R₇ is    -   a. hydrogen or    -   b. C₁-C₆-alkyl;    -   or R₆ and R₇ can form a 3 to 8-membered heterocycloalkyl with        the N to which they are attached to and wherein the        heterocycloalkyl is optionally substituted with C₁-C₆-alkyl;    -   R₈ is selected from    -   a. hydrogen;    -   b. hydroxy;    -   c. C₁-C₆-alkyl optionally substituted with hydroxy;    -   d. C(O)O—C₁-C₆-alkyl; and    -   e. —NH₂;    -   R₉ is selected from    -   a. C₃-C₈-cycloalkyl optionally substituted with an unsubstituted        C₁-C₆-alkyl;    -   b. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from N and O optionally substituted with C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl having a heteroatom selected from        N and O optionally substituted with C₁-C₆-alkyl;    -   d. phenyl;    -   R₁₀, R₁₁ and R₁₂ are each independently selected from    -   a. hydrogen;    -   b. halogen;    -   c. hydroxy;    -   d. C₁-C₆-alkyl;    -   e. C₁-C₆-alkoxy;    -   f. cyano;    -   g. —C(O)NH(C₁-C₆-alkyl)amino wherein the amino is —N(CH₃)₂); and    -   h. —NH₂.

Any of the above chemical groups can be optionally substituted as laidout in the below definitions.

According to another aspect of the invention, are providedtriazolopyridine compound intermediates.

According to another aspect of the invention, are providedtriazolopyridine compounds according to Formula (I) for use asmedicament.

According to another aspect of the invention, are providedpharmaceutical formulations comprising triazolopyridine compoundsaccording to Formula (I).

According to another aspect of the invention, are providedtriazolopyridine compounds according to Formula (I), which are able tomodulate, especially inhibit the activity or function of ASK, inparticular ASK-1, in disease states in mammals, especially in humans.

According to another aspect of the invention, are provided methods forthe prevention or treatment of autoimmune diseases, inflammatorydiseases, cardiovascular diseases and/or neurodegenerative diseases byadministering an effective amount of a triazolopyridine compoundsaccording to Formula (I) to a subject in need thereof.

According to another aspect of the invention, are provided methods forthe prevention or treatment of autoimmune diseases, inflammatorydiseases, cardiovascular diseases and/or neurodegenerative diseases byadministering an effective amount of a triazolopyridine compoundsaccording to Formula (I) to a subject in need thereof, by modulating,especially inhibiting the activity or function of ASK.

According to another aspect of the invention, is provided a process forthe preparation of a triazolopyridine compound according to Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

The term “alkyl” refers to a linear or branched saturated hydrocarbonchain; this term is exemplified by groups such as methyl; ethyl;n-propyl; isopropyl; n-butyl; isobutyl; tert-butyl; n-hexyl. The term“C₁-C₆-alkyl” refers to alkyl groups having 1 to 6 carbon atoms.

The term “alkenyl” refers to unsaturated alkyl groups having at leastone double bond and includes both linear- and branched alkenyl groups;this term is exemplified by groups such as propenyl, but-3-enyl,pent-4-enyl.

The term “C₂-C₆ alkenyl” refers to alkenyl groups having from 2 to 6carbon atoms.

The term “aryl” refers to an aromatic carbocyclic group having at leastone aromatic ring (e.g. phenyl or biphenyl) or multiple condensed ringsin which at least one ring is aromatic, (e.g. naphthyl, anthryl, orphenanthryl).

The term “heteroaryl” refers to a monocyclic heteroaromatic, or abicyclic or a tricyclic fused-ring heteroaromatic group, wherein the atleast one heteroatom selected from nitrogen, oxygen, and sulfur.C₃-C₈-heteroaryl, C₃-C₁₀-heteroaryl etc. refers to the size of thecorresponding heteroaryl. Particular examples of heteroaromatic groupsinclude e.g., 2,3-dihydro benzofuranyl, 1-oxidopyridinyl,2,3-dihydro-1,4-benzodioxinyl, quinoxalinyl,2,2-difluoro-1,3-benzodioxolyl, pyridinyl, pyrrolyl, furanyl,thiophenyl, isoxazolyl, pyrazolyl, benzofuryl, [2,3-dihydro]benzofuryl,benzoxazolyl, quinoxalinyl.

The term “cycloalkyl” refers to alkyl groups having a monocyclic ring,bicyclic or multiple fused alkyl rings; such cycloalkyl rings includee.g. cyclopropyl, cyclobutyl, cyclopentyl; cyclohexyl, cycloheptyl,cyclooctyl; and the like; such multiple ring structures include e.g.adamantanyl; and bicyclo[2.2.1]heptane. “C₃-C₈”, “C₃-C₁₀” etc. refers tothe cycle size of the corresponding cycloalkyl.

The term “heterocycloalkyl” means a non-aromatic monocyclic orpolycyclic ring comprising carbon and hydrogen atoms and at least oneheteroatom selected from nitrogen, oxygen, and sulfur.“C₃-C₈”-heterocycloalkyl, “C₃-C₁₀” etc. refers to the size of thecorresponding heterocycloalkyl. Particular examples of heterocycloalkylgroups include e.g. tetrahydrofuranyl, tetrahydro-2H-pyranyl,morpholinyl, pyrrolidinyl, piperidinyl, 2-oxopyrrolidinyl, piperazinyl.

The term “halogen” refers to Br, Cl, I, F.

The term “cyano” refers to a —C≡N group.

The term “perfluoroC₁-C₆-alkyl” refers to a C₁-C₆-alkyl group whereineach hydrogen atom has been replaced by a fluoro atom.

The term “amino” refers to a —NRR′ group wherein R and R′ are eachindependently selected from a) hydrogen, b) C₁-C₆-alkyl optionallysubstituted with hydroxy, C₁-C₆-alkoxy, c) heteroaryl-C₁-C₆-alkylwherein the heteroatom is O, d) acylamino-C₁-C₆-alkyl, e)—C(O)OC₁-C₆-alkyl.

The term “acyl” refers to a group —C(O)R wherein R is H, C₁-C₆-alkyl orphenyl.

The term “amido” refers to a group —C(O)—NRR′ wherein R and R′ areindependently H or C₁-C₆-alkyl, and may form a cycle with the N to whichthey are attached.

The term “C₁-C₆-alkylamino” refers to a C₁-C₆-alkyl group attached tothe parent molecular group through an amino.

The term “amino-C₁-C₆-alkyl” refers to an amino group attached to theparent molecular group through a C₁-C₆-alkyl wherein the amino group isselected from —NH₂, —NHC₁-C₆-alkyl, and —N(C₁-C₆-alkyl)₂ wherein the twosubstituents C₁-C₆-alkyl can be the same or different, and wherein thetwo substituents may form a 3 to 8-membered heterocycloalkyl with the Nto which they are attached to and which heterocycloalkyl may beoptionally substituted with C₁-C₆-alkyl.

The term “alkyloxy” or “alkoxy” refers to the group —OR (e.g. methoxy,ethoxy) wherein R is alkyl.

The term “cycloalkyl-oxy” or “cycloalkoxy” refers to a group —O—R (e.g.cyclohexyloxy) wherein R is a cycloalkyl.

The term “cycloalkyl-sulfanyl” refers to a group —S—R (e.g.cyclohexylsulfanyl) wherein R is a cycloalkyl.

The term “cycloalkyl-C₁-C₆-alkyl” refers to a cycloalkyl group attachedto the parent molecular group through a C₁-C₆-alkyl.

The term “aryl-C₁-C₆-alkyl” refers to an aryl group attached to theparent molecular group through a C₁-C₆-alkyl (e.g. benzyl).

The term “aryl-C₁-C₆-alkyloxy” refers to a —O—R group wherein R is arylC₁-C₆-alkyl (e.g. benzyloxy).

The term “heteroaryl-C₁-C₆-alkyl” refers to a heteroaryl group attachedto the parent molecular group through a C₁-C₆alkyl.

The term “—C(O)Oalkyl” or “alkoxycarbonyl” refers to a group —C(O)—O—Rwherein R is a C₁-C₆-alkyl.

The term carboxylic acid refers to a —COOH.

The term “hydroxy-C₁-C₆-alkyl” refers to a C₁-C₆-alkyl substituted by ahydroxyl.

The term “heterocycloalkyl-C₁-C₆-alkyl” refers to a heterocycloalkylgroup attached to the parent molecular group through a C₁-C₆-alkyl.

The term “halogen-aryl” refers to a group aryl (e.g phenyl) substitutedby a halogen (e.g. 4-chloro-phenyl, 3-iodo-phenyl, 4-fluoro-phenyl,4-bromo-phenyl, 3-chloro-phenyl, 2-bromo-phenyl).

The term “C₁-C₆-alkyl-sulfonyl” refers to a group —S(O)₂—R wherein R isC₁-C₆-alkyl.

The term “acylamino-C₁-C₆-alkyl” refers to an acylamino group attachedto the parent molecular group through a C₁-C₆-alkyl.

The term “acylamino” refers to a group —NH-acyl group which may also bedefined as —NHC(O)R wherein R is a C₁-C₆-alkyl.

The above defined residues can be substituted or unsubstituted; the term“unsubstituted or substituted” or “optionally substituted” means thatunless otherwise constrained by the definition of the individualsubstituent, the above set out groups, like “alkyl”, “alkenyl”,“alkynyl”, “aryl”, “heteroaryl”, “cycloalkyl”, “heterocycloalkyl” etc.can be substituted with at least one substituent selected from the groupconsisting of “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“cycloalkyl”, “heterocycloalkyl”, “C₁-C₆-alkyl aryl”, “C₁-C₆-alkylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”,“amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”,“alkoxycarbonyl”, “ureido”, “aryl”, “—C(O)OC₁-C₆-alkyl”, “heteroaryl”,“sulfonyl”, “alkoxy”, in particular “C₁-C₆-alkoxy”, “sulfanyl”,“halogen”, “carboxy”, “trihalomethyl”, “cyano”, “hydroxy”, “mercapto”,“nitro”, “halogen-aryl”, “lactam”, in particular “γ-lactam” or“δ-lactam”, and the like.

“Pharmaceutically acceptable salts or complexes” refer to salts orcomplexes of the compounds disclosed herein. Examples of such saltsinclude, but are not limited to, salts which are formed with inorganicacids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, nitric acid, and the like), as well as salts formedwith organic acids such as acetic acid, oxalic acid, tartaric acid,succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid,benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamicacid, naphthalene sulfonic acid, methane sulfonic acid, naphthalenedisulfonic acid, and poly-galacturonic acid, as well as salts formedwith basic amino acids such as lysine or arginine.

Additionally, salts of compounds containing a carboxylic acid or otheracidic functional group(s) can be prepared by reacting with a suitablebase. Such a pharmaceutically acceptable salt may be made with a basewhich affords a pharmaceutically acceptable cation, which includesalkali metal salts (especially sodium and potassium), alkaline earthmetal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine,quinine, quinoline, and basic amino acid such as lysine and arginine.

According to one aspect of the invention, are provided triazolopyridinecompounds according to Formula (I):

-   -   wherein    -   R₁ is selected from    -   a. hydrogen;    -   b. C₁-C₆-alkyl;    -   c. C₂-C₆-alkenyl optionally substituted with C₁-C₆-alkyl;    -   d. —NR₆R₇;    -   e. C₃-C₈-cycloalkoxy, C₁-C₆-alkoxy;    -   f. C₃-C₈-cycloalkyl sulfanyl, C₁-C₆-alkyl sulfanyl; and    -   g. 5 or 6-membered heteroaryl having at least one heteroatom        selected from N, S and O, said heteroaryl being optionally        substituted with C₁-C₆ alkyl, halogen, or C₁-C₆ alkoxy;    -   R₂ is selected from    -   a. hydrogen;    -   b. halogen;    -   c. aryl optionally substituted with R₁₀, R₁₁ and/or R₁₂; and    -   d. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N, 5 and O and optionally substituted with C₁-C₆        alkyl;    -   or R₁ and R₂ taken together form a —C═C—C═C— group-;    -   R₃ is selected from    -   a. hydrogen;    -   b. halogen; and    -   c. C₁-C₆-alkyl optionally substituted with at least one fluoro;    -   R₄ is selected from    -   a. hydrogen; and    -   b. 5 or 6-membered heteroaryl having at least one heteroatom        selected from N, S and O;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NC(O)R′ wherein R′ is aryl optionally substituted with            C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆-cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxy carbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NHC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy;        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O;        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N, O or S optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl,        -   iii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl or —N(C₁-C₆-alkyl)₂, wherein the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or hydroxy;        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;        -   vii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N optionally substituted with            hydroxy, —C(O)OR′ wherein R′ is C₁-C₆-alkyl, halogen or            C₁-C₆-alkyl;        -   viii. amino;        -   ix. —NH(amino-C₁-C₆-alkyl);        -   x. —N(C₁-C₆-alkyl)₂;    -   R₆ is selected from    -   a. C₁-C₆-alkyl optionally substituted with one or two hydroxy        groups,    -   b. phenyl optionally substituted with at least one of the        following groups        -   i. halogen        -   ii. C₁-C₆-alkyl, or        -   iii. C₁-C₆-alkoxy;    -   c. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from O and N optionally substituted with C₁-C₆-alkyl;    -   d. C₃-C₈-cycloalkyl optionally substituted with R₈; and    -   e. —(CH₂)_(n)R₉ wherein n equals 1, 2 or 3;    -   R₇ is    -   a. hydrogen or    -   b. C₁-C₆-alkyl;    -   or R₆ and R₇ can form a 3 to 8-membered heterocycloalkyl with        the N to which they are attached to and wherein the        heterocycloalkyl is optionally substituted with C₁-C₆-alkyl;    -   R₈ is selected from    -   a. hydrogen;    -   b. hydroxy;    -   c. C₁-C₆-alkyl optionally substituted with hydroxy;    -   d. C(O)O—C₁-C₆-alkyl; and    -   e. —NH₂;    -   R₉ is selected from    -   a. C₃-C₈-cycloalkyl optionally substituted with an unsubstituted        C₁-C₆-alkyl;    -   b. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from N and O optionally substituted with C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl having a heteroatom selected from        N and O optionally substituted with C₁-C₆-alkyl;    -   d. phenyl;    -   R₁₀, R₁₁ and R₁₂ are each independently selected from    -   a. hydrogen;    -   b. halogen;    -   c. hydroxy;    -   d. C₁-C₆-alkyl;    -   e. C₁-C₆-alkoxy;    -   f. cyano;    -   g. —C(O)NH(C₁-C₆-alkyl)amino wherein the amino is —N(CH₃)₂); and    -   h. —NH₂.

Any of the above chemical groups can be optionally substituted.

The compounds according to the invention advantageously inhibit ASK,preferably ASK1. The inventors could achieve good IC₅₀ values by theparticular design of the compounds according to the invention.

The IC₅₀ value of the compounds of the invention measured according tothe procedure as outlined in the experiments is 30 μM or less,preferably 20 μM or less, more preferably 15 μM or less, even morepreferably 10 μM or less, still more preferably 5 μM or less, and morepreferably 1 μM or less.

It was found by the inventors that by refining the design of thecompounds in particular positions with a selection of chemical groups aswill be evident from the below description advantageous IC₅₀ values inthe nanomolar range could be achieved. Preferred compounds of theinvention exhibit an IC₅₀ value of, e.g. 900 nM or less, 700 nM or less,500 nM or less, 200 nM or less, 100 nM or less, 50 nM or less.

The compounds according to the invention are also characterized by theirpositive inhibitory effect in the Lipopolysaccharide (LPS)-induced TNFαrelease assay in mice as described in the below experimental section.Preferably the compounds of the invention exhibit an inhibition of 30%or more, preferably 40% or more, and more preferably 50% or more.

The dosage of a compound according to the invention applied in thisassay is usually between 10 and 80 mg/kg body weight. Another dosagethat may be used is between 20 and 60, preferably between 30 and 40mg/kg.

Other in vitro and in vivo assays known to the person skilled in the artmay be applied to show the positive effects of the compounds of theinvention and their relevance for various diseases. These models areapparent and well known to the person skilled in the field.

In the following, compounds and compound groups according to theinvention are described characterized by particular structural andfunctional features. Each of these compound groups exhibits alsoproperties making them useful for particular applications, e.g.particular medical indications, which will be evident by normalexperimentation available to the skilled person.

In one embodiment the invention relates to a triazolopyridine compoundaccording to Formula I wherein

-   -   R₁ is selected from    -   a. hydrogen;    -   b. C₁-C₆-alkyl;    -   c. C₂-C₆-alkenyl optionally substituted with C₁-C₆-alkyl;    -   d. —NR₆R₇;    -   e. C₃-C₈-cycloalkoxy;    -   f. C₃-C₈-cycloalkyl sulfanyl; and    -   g. 5 or 6-membered heteroaryl having at least one heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl;    -   R₂ is selected from    -   a. hydrogen;    -   b. Cl or Br;    -   c. aryl optionally substituted with R₁₀, R₁₁ and/or R₁₂; and    -   d. 5, 6 or 9-membered heteroaryl having at least one heteroatom        selected from N, S and O and optionally substituted with C₁-C₆        alkyl;    -   or R₁ and R₂ taken together form a —C═C—C═C— group-;    -   R₃ is selected from    -   a. hydrogen;    -   b. chloro; bromo;    -   c. methyl; and    -   d. CF₃;    -   R₄ is selected from    -   a. hydrogen; and    -   b. furanyl;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NHC(O)R′ wherein R′ is aryl optionally substituted            with C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆ cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxy carbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy,        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O,        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl optionally substituted with a 5 or            6-membered heterocycloalkyl having at least one heteroatom            selected from O and N,        -   iii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;        -   vii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N optionally substituted with            hydroxy, —C(O)OR′ wherein R′ is C₁-C₆-alkyl, halogen or            C₁-C₆-alkyl,        -   viii. amino,        -   ix. —NH(amino-C₁-C₆-alkyl),        -   x. —N(C₁-C₆-alkyl)₂;    -   R₆ is selected from    -   a. C₁-C₆-alkyl optionally substituted with one or two hydroxy        groups,    -   b. phenyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl, or        -   iii. C₁-C₆-alkoxy;    -   c. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from O and N optionally substituted with is C₁-C₆-alkyl;    -   d. C₃-C₈-cycloalkyl optionally substituted with R₈; and    -   e. —(CH₂)_(n)R₉ wherein n equals 1, 2 or 3;    -   R₇ is    -   a. hydrogen or    -   b. C₁-C₆-alkyl; or    -   or R₆ and R₇ can form a 3 to 8-membered heterocycloalkyl with        the N to which they are attached to and wherein the        heterocycloalkyl is optionally substituted with C₁-C₆-alkyl;    -   R₈ is selected from    -   a. hydrogen;    -   b. hydroxy;    -   c. unsubstituted or substituted C₁-C₆-alkyl wherein the        substituent is hydroxyl;    -   d. C(O)O—C₁-C₆-alkyl; and    -   e. —NH₂;    -   R₉ is selected from    -   a. C₃-C₈-cycloalkyl optionally substituted with an unsubstituted        C₁-C₆-alkyl;    -   b. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from N and O optionally substituted with C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl having a heteroatom selected from        N and O optionally substituted with C₁-C₆-alkyl; and    -   d. phenyl.    -   R₁₀, R₁₁ and R₁₂ are each independently selected from    -   a. hydrogen;    -   b. fluoro, bromo;    -   c. hydroxyl;    -   d. C₁-C₆-alkyl;    -   e. C₁-C₆-alkoxy;    -   f. cyano;    -   g. —C(O)NH(C₁-C₆-alkyl)amino wherein the amino is —N(CH₃)₂); and    -   h. —NH₂.

In another embodiment the invention relates to triazolopyridinecompounds according to the following Formula I-1

-   -   wherein    -   R₂ is hydrogen or bromo;    -   R₃ is selected from    -   a. hydrogen;    -   b. halogen; and    -   c. C₁-C₆-alkyl optionally substituted with at least one fluoro;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NHC(O)R′ wherein R′ is aryl optionally substituted            with C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆ cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with        -   i. C₁-C₆-alkyl optionally substituted with a γ-lactam or            δ-lactam,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxycarbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NHC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy,        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O,        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl optionally substituted with a 5 or            6-membered heterocycloalkyl having at least one heteroatom            selected from O and N,        -   iii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;    -   R₆ is selected from    -   a. C₁-C₆-alkyl optionally substituted with one or two hydroxy        groups,    -   b. phenyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl,        -   iii. C₁-C₆-alkoxy;    -   c. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from O and N optionally substituted with is C₁-C₆-alkyl;    -   d. C₃-C₈-cycloalkyl optionally substituted with R₈; and    -   e. —(CH₂)_(n)R₉ wherein n equals 1, 2 or 3;    -   R₇ is    -   a. hydrogen or    -   b. C₁-C₆-alkyl.

In another embodiment the invention relates to triazolopyridinecompounds according to the following Formula I-2

-   -   wherein    -   R₃ is selected from    -   a. hydrogen;    -   b. halogen; and    -   c. C₁-C₆-alkyl optionally substituted with at least one fluoro;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NHC(O)R′ wherein R′ is aryl optionally substituted            with C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆ cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with        -   i. C₁-C₆-alkyl optionally substituted with a γ-lactam or            δ-lactam,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxycarbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NHC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy;        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O;        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl optionally substituted with a 5 or            6-membered heterocycloalkyl having at least one heteroatom            selected from O and N,        -   iii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;    -   R₆ is selected from    -   a. C₁-C₆-alkyl optionally substituted with one or two hydroxy        groups,    -   b. phenyl optionally substituted with at least one of the        following groups        -   i. halogen        -   ii. C₁-C₆-alkyl,        -   iii. C₁-C₆-alkoxy;    -   c. 5 or 6-membered heterocycloalkyl having a heteroatom selected        from O and N optionally substituted with is C₁-C₆-alkyl;    -   d. C₃-C₈-cycloalkyl optionally substituted with R₈; and    -   e. —(CH₂)_(n)R₉ wherein n equals 1, 2 or 3.    -   R₈ and R₉ are as above defined.

Compounds according to Formula I-2 as defined above exhibit an IC₅₀ of20 μM or less, preferably 15 μM or less, more preferably 10 μM or less,even more preferably 5 μM or less and even more preferably 1 μM or less.

Preferred embodiments of the above Formula I-2 are:

-   -   1. wherein R₃ is Cl, Br, —CH₃ or —CF₃;    -   2. wherein R₃ is Cl, Br, —CH₃ or —CF₃.    -   R₅ is selected from    -   a. phenyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl,        -   ii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxy carbonyl,        -   iii. —NHC(O)C₁-C₆-alkyl,        -   iv. —N(C₁-C₆-alkyl)₂,        -   v. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O optionally substituted with            C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy        -   vi. C₁-C₆-alkoxy,        -   vii. halogen; and    -   b. pyridinyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl optionally substituted with a 5 or 6-membered            heterocycloalkyl having at least one heteroatom selected            from O and N,        -   ii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iii. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   iv. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;    -   R₆ is selected from    -   a. unsubstituted C₁-C₆-alkyl,    -   b. phenyl optionally substituted with at least one of the        following groups        -   i. halogen, preferably F, Cl,        -   ii. C₁-C₆-alkyl,        -   iii. C₁-C₆-alkoxy,    -   c. 6-membered heterocycloalkyl having a heteroatom selected from        O and N optionally substituted with C₁-C₆-alkyl;    -   d. C₃-C₈-cycloalkyl optionally substituted with C₁-C₆-alkyl.    -   3. wherein R₃ is Cl, Br, —CH₃ or —CF₃;    -   R₅ is selected from    -   a. phenyl optionally substituted with amino-C₁-C₆-alkyl wherein        amino is selected from        -   i. —NH₂,        -   ii. —NHC₁-C₆-alkyl,        -   iii. —N(C₁-C₆-alkyl)₂, and        -   iv. 5 or 6-membered heterocycloalkyl having as heteroatom N            or O;    -   b. pyridinyl;    -   c. and pyridin-C₁-C₆-alkyl;    -   R₆ is selected from    -   a. C₁-C₆-alkyl optionally substituted with        -   i. hydroxy, or        -   ii. C₁-C₆-alkoxy;    -   b. C₃-C₈-cycloalkyl;    -   c. —CH₂R₉ wherein R₉ is C₃-C₆-cycloalkyl.

These preferred embodiments of the invention preferably exhibit an IC₅₀of 5 μM or less, preferably 1 μM or less, more preferably 0.9 μM orless, even more preferably 0.5 μM or less, even more preferably 0.3 μMor less and still preferably 0.1 μM or less.

In another embodiment the invention relates to triazolopyridinecompounds according to the following Formula I-3

-   -   wherein    -   R₁ is selected from    -   a. hydrogen;    -   b. unsubstituted C₁-C₆-alkyl;    -   c. C₂-C₆-alkenyl optionally substituted with C₁-C₆-alkyl;    -   d. —NR₆R₇;    -   e. unsubstituted C₃-C₈-cycloalkoxy;    -   f. unsubstituted C₃-C₈-cycloalkyl sulfanyl; and    -   g. 5 or 6 membered heteroaryl having at least one heteroatom        selected from N, S and O optionally substituted with C₁-C₆        alkyl;    -   R₂ is hydrogen or bromo;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NHC(O)R′ wherein R′ is aryl optionally substituted            with C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆ cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with        -   i. C₁-C₆-alkyl optionally substituted with a γ-lactam or            δ-lactam,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxycarbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NHC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy,        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O,        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl optionally substituted with a 5 or            6-membered heterocycloalkyl having at least one heteroatom            selected from O and N,        -   iii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N.

In another embodiment the invention relates to triazolopyridinecompounds according to the following Formula I-4

-   -   wherein    -   R₁ is selected from    -   a. unsubstituted C₁-C₆-alkyl;    -   b. C₂-C₆-alkenyl optionally substituted with C₁-C₆-alkyl;    -   c. —NR₆R₇;    -   d. unsubstituted C₃-C₈-cycloalkoxy;    -   e. unsubstituted C₃-C₈-cycloalkyl sulfanyl; and    -   f. 5 or 6 membered heteroaryl having at least one heteroatom        selected from N, S and O optionally substituted with C₁-C₆        alkyl;    -   R₅ is selected from    -   a. C₁-C₆-alkyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkoxycarbonyl,        -   ii. C₁-C₆-alkoxy,        -   iii. —NHC(O)R′ wherein R′ is aryl optionally substituted            with C₁-C₆-alkyl,        -   iv. benzyloxy;    -   b. aryl-C₁-C₆-alkyl;    -   c. 5 or 6-membered heteroaryl-C₁-C₆-alkyl having a heteroatom        selected from N, S and O optionally substituted with        C₁-C₆-alkyl, halogen or C₁-C₆-alkoxy;    -   d. C₃-C₆ cycloalkyl optionally substituted with phenyl;    -   e. 3 to 8-membered heterocycloalkyl having a heteroatom selected        from N, S and O optionally substituted with an acyl group;    -   f. aryl optionally substituted with        -   i. C₁-C₆-alkyl optionally substituted with a γ-lactam or            δ-lactam,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. at least one C₁-C₆-alkoxy optionally substituted with            C₁-C₆-alkoxycarbonyl,        -   iv. phenyl,        -   v. C₁-C₆-alkyl sulfonyl,        -   vi. —NHC(O)C₁-C₆-alkyl,        -   vii. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,            N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two            substituents C₁-C₆-alkyl can be the same or different, and            wherein the two substituents may form a 3 to 8-membered            heterocycloalkyl with the N to which they are attached to            and wherein the heterocycloalkyl is optionally substituted            with C₁-C₆-alkyl or with hydroxy,        -   viii. —N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl),        -   ix. 5 to 6-membered heterocycloalkyl-C₁-C₆-alkyl having a            heteroatom selected from N and O,        -   x. amido-C₁-C₆-alkyl,        -   xi. C₁-C₆-alkoxy,        -   xii. halogen;    -   g. 5 to 10-membered heteroaryl having at least one heteroatom        selected from N optionally substituted with halogen; and    -   h. pyridinyl optionally substituted with at least one of the        following groups        -   i. halogen,        -   ii. C₁-C₆-alkyl optionally substituted with a 5 or            6-membered heterocycloalkyl having at least one heteroatom            selected from O and N,        -   iii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iv. —NH(hydroxy-C₁-C₆-alkyl),        -   v. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   vi. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N;

Preferably these compounds exhibit an IC₅₀ of 20 μM or less, preferably5 μM or less, more preferably 10 μM or less, even more preferably 5 μMor less.

A preferred embodiment of the above Formula I-4 is where

-   -   R₁ is an unsubstituted 5-membered heteroaryl having at least one        heteroatom selected from O, S and N;    -   R₅ is selected from    -   a. phenyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl,        -   ii. perfluoro-C₁-C₆-alkyl,        -   iii. C₁-C₆-alkoxy;        -   iv. C₁-C₆-alkoxy,        -   v. halogen; and    -   b. pyridinyl optionally substituted with at least one of the        following groups        -   i. Cl,        -   ii. Br,        -   iii. —NH(hydroxy-C₁-C₆-alkyl).

Preferably these compounds exhibit an IC₅₀ of 15 μM or less, morepreferably 10 μM or less, even more preferably 5 μM or less, even morepreferably 1 μM or less, and still more preferably 0.9 μM or less.

In another embodiment the invention relates to triazolopyridinecompounds according to the following Formula I-5

-   -   wherein    -   R₂ is selected from    -   a. phenyl optionally substituted with        -   i. at least one unsubstituted C₁-C₆-alkyl,        -   ii. unsubstituted C₁-C₆-alkoxy,        -   iii. fluoro,        -   iv. bromo,        -   v. hydroxy,        -   vi. cyano, or        -   vii. —NH₂; and    -   b. 5 or 9-membered heteroaryl having a heteroatom selected from        N, S and O;    -   R₅ is selected from    -   a. unsubstituted C₁-C₆-alkyl;    -   b. aryl optionally substituted with        -   i. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆alkyl or —N(C₁-C₆-alkyl)₂, and the two substituents            C₁-C₆-alkyl may form a 3 to 8-membered heterocycloalkyl with            the N to which they are attached to and wherein the            heterocycloalkyl is optionally substituted with C₁-C₆-alkyl,        -   or        -   ii. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl; and    -   c. pyridinyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl optionally substituted with a 5 or 6-membered            heterocycloalkyl having at least one heteroatom selected            from O and N,        -   ii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iii. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   iv. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N.

Preferably these compounds exhibit an IC₅₀ of 20 μM or less, morepreferably 15 μM or less, even more preferably 10 μM or less, and evenmore preferably 5 μM or less.

A preferred embodiment of the above Formula I-5 is where

-   -   R₂ is selected from    -   a. phenyl optionally substituted with at least one of the        following groups        -   i. at least one unsubstituted C₁-C₆-alkyl,        -   ii. unsubstituted C₁-C₆-alkoxy,        -   iii. fluoro,        -   iv. bromo,        -   v. hydroxy,        -   vi. cyano        -   vii. —NH₂;    -   b. furanyl; and    -   c. thienyl;    -   R₅ is selected from    -   a. unsubstituted C₁-C₆-alkyl;    -   b. phenyl optionally substituted with        -   i. amino-C₁-C₆-alkyl wherein amino is selected from —NH₂,            —NHC₁-C₆-alkyl or —N(C₁-C₆-alkyl)₂, or        -   ii. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl;    -   c. pyridinyl optionally substituted with at least one of the        following groups        -   i. C₁-C₆-alkyl optionally substituted with a 5 or 6-membered            heterocycloalkyl having at least one heteroatom selected            from O and N,        -   ii. 5 or 6-membered heterocycloalkyl having at least one            heteroatom selected from O and N,        -   iii. —NH-(5-membered heteroaryl-C₁-C₆-alkyl having as            heteroatom O),        -   iv. 5 or 6-membered heterocycloalkyl-C₁-C₆-alkyl having at            least one heteroatom selected from O and N.

Preferably these compounds exhibit an IC₅₀ of 20 μM or less, morepreferably 15 μM or less, even more preferably 10 μM or less, even morepreferably 5 μM or less, and even more preferably 1 μM or less.

In another embodiment the invention relates to triazolopyridinecompounds according to the following Formula I-6

-   -   wherein    -   R₄ is furanyl;    -   R₅ is selected from unsubstituted phenyl; and 5 or 6-membered        heteroaryl having a heteroatom selected from N, S and O.

A preferred embodiment of the above Formula I-6 is wherein R₅ isselected from phenyl and 5-membered heteroaryl having a heteroatomselected from N, S and O.

In one embodiment R₁ is hydrogen; furanyl, preferably furan-2-yl, morepreferably furan-3-yl; or —NR₆R₇; R₂ is hydrogen, ormethoxy-hydroxy-phenyl, preferably 1H pyrazol-4-yl; R₃ isperfluoromethyl, Cl or Br; R₄ is hydrogen; R₅ is unsubstituted orsubstituted pyridine wherein the substituent is halogeno, preferably Clor Br; dihydro-1,4-benzodioxin-6-yl, 3,5-bis(methoxy)phenyl; phenyl; or4-(morpholoin-4-yl methyl)phenyl; Either of R₆ and R₇ is hydrogen;cycloalkyl, preferably cyclopropyl, more preferably cyclohexyl;cyclohexyl C₁-C₆-alkyl; C₁-C₆-alkyl, preferably methyl, more preferablyisobutyl, even more preferably isopropyl. The remaining chemical groupsare as earlier defined.

These compounds according to the invention are preferably characterizedby an IC₅₀ of 5 μM or less, preferably of 1 μM or less.

The embodiments of Formulae I-1, I-2, I-3, I-4, I-5 and I-6 and theembodiments thereof described as preferred may bear in further preferredembodiments at each chemical moiety substituents as described in thedefinitions regarding substituents above.

It was found by the inventors that the combination of these specificchemical groups leads to triazolopyridine compounds exhibiting very goodinhibition properties to its target, i.e. the ASK target, in particularto ASK1.

One structure of the compounds according to the invention ischaracterized by cycloalkyl, aryl or heteroaryl groups for R₁ or R₂ andR₅ wherein the remaining chemical groups are as defined above. Yetanother structure is a substituted cycloalkyl, a substituted aryl or asubstituted heteroaryl group for R₁ or R₂ and a substituted aryl orheteroaryl group for R₅ wherein the substituent is defined as above.

These structures of the compounds according to the invention exhibitgood inhibition of the target ASK, in particular ASK1, which is obviousfrom the advantageous IC₅₀ values as exemplified in the experimentalsection below. Moreover, such compounds show positive results, i.e.inhibition, in in vivo assays as exemplified by the LPS-induced TNFαrelease assay.

In this assay it could be shown that compounds according to theinvention as defined in this section characterized by the structuralfeatures as outlined above exhibit an in vivo inhibition of at leastabout 40%, preferably at least about 50%. Particularly good resultscould be achieved with compounds of the invention according to FormulaI-3 and Formula I-4 that may achieve an in vivo inhibition of at leastabout 40%, preferably at least about 42%, more preferably at least about45%, and even more preferably at least about 48%. A particular group ofcompounds is characterized by —NR₆R₇ with R₆ and R₇ as defined above ora 5 or 6 membered heteroaryl in position R₁ and a pyridinyl in positionR₅ that exhibit an in vivo inhibition of at least about 43%, preferablyat least about 48%.

The structural motif as described in the above section may even enhancethe properties by additional groups such as —CF₃ or a halogen inpositions R₂ or R₃.

In particular advantageous is a perfluoromethyl group for R₃ and/or afuranyl for R₁ and/or a pyridine for R₅. Such compounds are preferablycharacterized by positive IC₅₀ values of e.g. 10 μM ore less, preferably5 μM or less, preferably 1 μM or less, more preferably of 0.1 μM or lessand even more preferably of 0.5 μM or less.

Advantageously, it was found by the inventors that the abovecharacterized positions play a significant role in the positiveinhibition effects of the inventive compounds to the target ASK.

The invention is further exemplified by the following triazolopyridinecompounds:

-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-phenylacetamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(trifluoromethyl)benzamide;-   ethyl    3-{[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropanoate;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-methoxyacetamide;-   6-chloro-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   methyl    4-{[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-4-oxobutanoate;-   2-(benzyloxy)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]acetamide;-   3-methoxy-N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentanecarboxamide;-   N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(1H-pyrazol-4-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[6-(3-fluorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-(6-phenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   N-[6-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[6-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-methoxybenzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-(2-thienyl)acetamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentanecarboxamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-methoxybenzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]isonicotinamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]quinoxaline-6-carboxamide;-   N-[6-(3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[6-(3-aminophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[6-(3-cyanophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]isoxazole-5-carboxamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[5-(cyclopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-(5-pyrrolidin-1-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3,5-dimethoxybenzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]biphenyl-4-carboxamide;-   1-(4-chlorophenyl)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentanecarboxamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,3-dihydro-1-benzofuran-5-carboxamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-furamide;-   1-acetyl-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]piperidine-4-carboxamide;-   2,2-difluoro-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1,3-benzodioxole-4-carboxamide;-   N-[5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[1,2,4]triazolo[1,5-a]quinolin-2-ylnicotinamide;-   N-[5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    1-oxide;-   N-{5-[(3-methoxypropyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   N-{5-[(2-furylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   N-{5-[(tetrahydrofuran-2-ylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   3-(acetylamino)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-(methylsulfonyl)benzamide;-   3-(aminomethyl)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-(5-{[1-(hydroxymethyl)propyl]amino}[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;-   N-[6-(3-hydroxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   tert-butyl[4-({[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)benzyl]carbamate;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-isobutylbenzamide;-   tert-butyl[4-({[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)phenoxy]acetate;-   4-butyl-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide    hydrochloride;-   N-{5-[(2-methoxyethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   N-{5-[(2,3-dihydroxypropyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   N-[6-(2,3-dihydro-1-benzofuran-5-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(benzylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    dihydrochloride;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-(5-{[(5-methyl-2-furyl)methyl]amino}[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   N-{5-[(tetrahydrofuran-2-ylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-[6-(4-hydroxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    hydrochloride;-   N-[5-(cyclooctylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-{5-[cyclohexyl(methyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-[5-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-{5-[(1-methylpiperidin-4-yl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-{5-[(3-aminocyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   N-{5-[(1-methylpiperidin-4-yl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cyclohexylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cycloheptylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cyclopentylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-[(cyclohexylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-(6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   N-{5-[(3-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-{5-[(4-tert-butylcyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-[5-(tetrahydro-2H-pyran-3-ylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(morpholin-4-ylmethyl)benzamide;-   N-[5-(cyclohexylthio)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-{5-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-[5-(cyclobutylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(dimethylamino)methyl]benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-(morpholin-4-ylmethyl)benzamide;-   N-[5-[(cyclopropylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   methyltrans-4-{[2-[(pyridin-3-ylcarbonyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-5-yl]amino}cyclohexanecarboxylate;-   N-[5-{[(1RS,2RS)-2-(hydroxymethyl)cyclohexyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[6-bromo-5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide;-   N-[5-(2-methylprop-1-en-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    dihydrochloride;-   N-(3-oxo-3-{[5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}propyl)benzamide;-   N-(3-{[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide;-   N-(3-{[5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide;-   N-(3-{[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide;-   N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(sec-butylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(methylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[8-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-(3-methoxyphenyl)acetamide;-   N-[5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4-ylmethyl)nicotinamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide;-   N-[5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]acetamide;-   N-[6-(4-hydroxy-3,5-dimethylphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   4-[2-(benzoylamino)[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-[2-(dimethylamino)ethyl]benzamide;-   N-[6-(1H-pyrazol-4-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-{5-[(cyclohexylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;-   N-{5-[(4-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-methoxybenz    amide;-   N-[5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-furamide;-   N-[7-chloro-5-(cyclobutylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[7-chloro-5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[7-chloro-5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[7-chloro-5-(cyclopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-[(2-methoxyethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-[(2-hydroxyethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(dimethylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperidin-1-ylmethyl)benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(pyrrolidin-1-ylmethyl)benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(2-furylmethyl)amino]nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    1-oxide;-   N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamide    trihydrochloride;-   N-[5-[(1-ethylpropyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    1-oxide;-   N-[5-[(3-hydroxycyclohexyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    formic acid;-   N-{7-chloro-5-[(3-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide    formic acid;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(dimethylamino)methyl]benzamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-pyrrolidin-1-ylnicotinamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;-   N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperidin-1-ylmethyl)benzamide;-   N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;-   N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide;-   4-[(dimethylamino)methyl]-N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-[5-{[(1R,2S)-2-(hydroxymethyl)cyclohexyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide    hydrochloride;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-hydroxypiperidin-1-yl)methyl]benzamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(pyrrolidin-1-ylmethyl)benzamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(4-hydroxypiperidin-1-yl)nicotinamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-piperazin-1-ylnicotinamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(dimethylamino)nicotinamide;-   N-[6-bromo-5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(dimethylamino)nicotinamide;-   tert-butyl    4-[5-({[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)pyridin-2-yl]piperazine-1-carboxylate;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-hydroxypiperidin-1-yl)methyl]benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(4-fluoropiperidin-1-yl)nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(1H-pyrazol-1-yl)nicotinamide;-   tert-butyl    4-[5-({[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)pyridin-2-yl]piperazine-1-carboxylate;-   N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide;-   N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4-ylmethyl)nicotinamide;-   N-[5-[(pyrrolidin-3-ylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperazin-1-ylmethyl)benzamide;-   N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-formylpiperazin-1-yl)methyl]benz    amide;-   N-[5-(piperidin-3-ylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(2-methoxyethyl)(methyl)amino]nicotinamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}benzamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;-   N-[7-chloro-5-(isopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-[(3-isopropoxyphenyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-[(3-fluoro-4-methoxyphenyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-{[3-(benzyloxy)phenyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(morpholin-4-ylmethyl)benzamide;-   N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;-   6-chloro-N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   6-[(2-aminoethyl)amino]-N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(sec-butylamino)-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N-[5-(isopropylamino)-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide.

In another aspect the invention relates to the following intermediatecompounds:

-   5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   tert-butyl    2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate;-   5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;-   N⁵-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;-   5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   [1,2,4]triazolo[1,5-a]quinolin-2-amine;-   6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;-   6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;-   5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   N⁵-isopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;-   N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;-   N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;-   N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;-   N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide    hydrochloride;-   N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   4-(chloromethyl)-N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;-   N-(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;-   N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;-   6-chloro-N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;-   N¹-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;-   5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine;-   N-(5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide.

In another aspect the invention relates to the use of triazolopyridinecompounds according to the invention for use as a medicament.

In another aspect the invention relates to a method for the preventionand/or treatment of autoimmune disorders, inflammatory diseases,cardiovascular diseases and/or neurodegenerative diseases in a subject,comprising administering to the subject an effective amount of acompound according to the invention.

The compounds according to the invention may be used for the preparationof a medicament for modulating and/or inhibiting the activity orfunction of ASK, in particular ASK-1, in a subject and in particular forpreventing and/or treating autoimmune disorders, inflammatory diseases,cardiovascular diseases and/or neurodegenerative diseases.

In another aspect the invention relates to a method for the preventionand/or treatment of autoimmune disorders, inflammatory diseases,cardiovascular diseases and/or neurodegenerative diseases in a subject,comprising administering to the subject an effective amount of acompound according to the invention in combination with other activecompounds useful in the same indication in order to achieve increasedefficacy.

In another aspect the compounds according to the invention mayadvantageously be used in a method for modulating and/or inhibiting theactivity or function of ASK, in particular ASK-1, in a subject,comprising administering to the subject an effective amount of one ormore of said compounds.

Another aspect of the invention is a pharmaceutical compositioncontaining at least one triazolopyridine compound according to theinvention and a pharmaceutically acceptable carrier, diluent orexcipient.

Another aspect of the invention is a process for the preparation of atriazolopyridine compound according to formula (I), comprising the stepof reacting a compound of Formula (II) with an acylating agent ofFormulas (IIIa or IIIb) in a presence of a base or a coupling agent:

wherein R₁, R₂, R₃, R₄, R₅ are as defined in any of the abovedefinitions, wherein the base is selected from tertiary amine bases suchas DIEA, TEA, NMM or pyridine, and the coupling agent is selected from apeptide coupling agent such as DCC, HATU, EDC/HOBt,i-butylchloroformate, carbonyl diimidazole, Mukaiyama's reagent in asuitable solvent such as DCM or CH₃CN; and optionally further purifyingthe obtained compound.

A further aspect is a process for the preparation of a triazolopyridinecompound according to formula (Ia) or (Ic), comprising A) the step ofreacting a compound of Formula (Ib) wherein R₁, R₂, R₃, R₄ are as abovedefined but at least one is a group X selected from a halogen such as F,Br, Cl, I or a sulfonate ester such as OTf, with a boronic agent offormula (IVa) or ester (IVb) wherein R′₁ is an optionally substitutedaryl, heteroaryl or alkenyl group as above defined in the presence of abase such as K₂CO₃, K₃PO₄ and a catalytic amount of a palladium catalystsuch as PdCl₂(PPh₃)₂ or Pd(OAc)₂ with a ligand such as DPPF in anappropriate solvent such as DMF, THF, dioxane or a combination of waterwith toluene, DMF, THF or dioxane to give a compound of formula (Ia)wherein at least one of R₁, R₂, R₃, R₄ is R′₁ or B) the step of reactinga compound of Formula (Id) wherein R₁ is a leaving group such as F, Cl,Br, I, OMs, OTf or SR₁₃ where R₁₃ is an alkyl group with a secondaryamine NHR₆R₇ of formula (V) wherein R₆ and R₇ are as above defined in apolar solvent such as ethanol or butanol or the amine itself to give acompound of formula (Ic) wherein R₁ is NR₅R₆, and optionally furtherpurifying the obtained compound.

Yet another aspect of the invention is a process for the preparation ofa triazolopyridine compound according to formula (IIa) wherein R₂, R₃,R₄, R₅ and R₆ are as above defined, comprising the step of reacting atriazolopyridine compound of Formula (IIb) wherein R₁ is a leaving groupsuch as F, Cl, Br, I, OMs, OTf or SR₁₃ where R₁₃ is an alkyl group witha secondary amine NHR₆R₇ of formula (V) wherein R₆ and R₇ are as abovedefined in a polar solvent such as ethanol or butanol or the amineitself to give a compound of formula (Ic) wherein R₁ is NR₅R₆; andoptionally further purifying the obtained compound.

Synthesis of Compounds of the Invention

The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz(Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM(millimolar), m.p. (melting point), eq. (equivalent), mL (milliliter),μL (microliter), ACN (acetonitrile), BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene), Boc (tert-Butoxycarbonyl), BuLi(Butyl Lithium), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate), c-Hex (Cyclohexane), DCC(Dicycloexylcarbodiimide), DCM (Dichloromethane), DEA (diethylamine),DIEA (Diisopropylethylamine), DMF (Dimethylformamide), DMSO (Dimethylsulfoxide), DMSO-d₆ (Deuterated dimethylsulfoxide), DPPF(1,1′-bis(diphenylphosphino)ferrocene), EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), EtOAc(Ethyl acetate), ESI (Electro-spray ionization), Et₂O (Diethyl ether),EtOH (Ethanol), HOBT (1-hydroxybenzotriazole), HPLC (High PerformanceLiquid Chromatography), i-PrOH (2-propanol), MS (mass spectrometry),MTBE (Methyl tert-butyl ether), MW (micro-wave irradiation), NMM(N-methylmorpholine), NMR (Nuclear Magnetic Resonance), OTf(trifluoromethanesulfonate), rt (room temperature), SPE (solid phaseextraction), TEA (Triethylamine), TFA (Trifluoroacetic acid), THF(Tetrahydrofuran), TLC (Thin Layer Chromatography).

The triazolopyridines compounds according to Formula (I) may be preparedfrom readily available starting materials using the following generalmethods and procedures. It will be appreciated that where typical orpreferred experimental conditions (i.e. reaction temperatures, time,moles of reagents, solvents, etc.) are given, other experimentalconditions can also be used unless otherwise stated.

Generally, the triazolopyridines compounds according to the generalFormula (I) may be obtained by several processes using bothsolution-phase and solid-phase chemistry protocols. Examples ofsynthetic pathways will be described. Optimum reaction conditions mayvary with the particular reactants or solvents used, but such conditionscan be determined by the person skilled in the art, using routineoptimisation procedures.

Depending on the nature of R₁, R₂, R₃, R₄ and R₅, different syntheticstrategies may be selected for the synthesis of compounds of Formula(I). In the process illustrated in the following schemes R₁, R₂, R₃, R₄and R₅ are as above-defined in the description.

In general, the synthesis pathways for any individual compound ofFormula (I) will depend on the specific substituents of each moleculeand upon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art. For allthe protection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

According to one process as of scheme 1, triazolopyridine compoundsaccording to the general Formula (I) whereby R₁, R₂, R₃, R₄ and R₅ aredefined as in any of the above definitions, are prepared from thecorresponding triazolopyridine amino compounds of formula (II) byreaction with an acylating agent of general Formula (III) whereby thesubstituent R₅ is as in any of the above definitions, while LG could beany appropriate leaving group such as Cl, OH. Preferred acylating agents(III) are acid chlorides (Ma) used in conjunction with a base such astertiary amine bases (e.g. DIEA, TEA, NMM), pyridine, or carboxylicacids (Mb), used in conjunction with a peptide coupling agent (insolution or solid supported) such as DCC, HATU, EDC/HOBt,i-butylchloroformate, carbonyl diimidazole, Mukaiyama's reagent in thepresence or the absence of a base such as DIEA, sodium tert-butyloxide.

A preferred condition for the preparation of a compound of Formula (I)whereby R₁, R₂, R₃, R₄ and R₅ are as in any of the above definitionsconsists in the reaction of triazolopyridines amino derivatives ofFormula (II) with an acid chloride (Ma) wherein R₅ is as defined above,in a suitable solvent such as DCM or CH₃CN at a temperature between 0°C. and 100° C. in the presence of pyridine.

According to a further general process, compounds of Formula (I) can beconverted to alternative compounds of Formula (I), employing suitableinterconversion techniques well known by a person skilled in the art.

A preferred method as of scheme 2 to prepare the triazolopyridinecompounds according to the general Formula (Ia) wherein R₁, R₂, R₃, R₄are as above defined but at least one is an aryl, a heteroaryl or analkenyl group R′₁, consist in reacting triazolopyridine compoundsaccording to the general Formula (Ib) wherein one of R₁, R₂, R₃ and R₄are as above defined, but at least one is a group X selected from ahalogen atom such as Cl, Br, I or a sulfonate ester such as OTf with aboronic acid (IVa) or ester (IVb) wherein R′₁ is as above defined usingwell known Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A.Chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., TetrahedronLett. 2005, 46, 3573-3577). In a typical procedure, triazolopyridinecompounds (Ib) and boronic acid (IVa) or ester (IVb) are heated atvarious temperature by traditional thermic methods or using microwavetechnology in presence of a base such as K₂CO₃, K₃PO₄ or CsF and acatalytic amount of palladium catalyst such as PdCl₂(PPh₃)₂ or Pd(OAc)₂with a ligand such as DPPF in an appropriate solvent such as DMF or acombination of water with THF or dioxane such as those describedhereinafter in the Examples.

A preferred method as of scheme 3 to prepare the triazolopyridinecompounds according to the general Formula (Ic) whereby R₂, R₃, R₄ andNR₆R₇ are as defined above, consists in reacting triazolopyridinecompounds according to the general Formula (Id) whereby R₂, R₃, R₄ andR₅ are as above defined and R₁ is F, Cl, Br, I, OMs, OTf or SR₁₃ whereR₁₃ is an alkyl group with an amine R₆R₇NH (V). In a typical procedure,triazolopyridine compounds according to the general Formula (Id) andamines R₆R₇NH (V) are heated at various temperature by traditionalthermic methods or using microwave technology in an appropriate solventsuch as ethanol, butanol or the amine itself such as those describedhereafter in the examples.

Triazolopyridine amino compounds of formula (II), whereby thesubstituent R¹, R², R³, and R⁴ are as above defined, are prepared from2-aminopyridine compounds of Formula (VI) by well known protocols suchas shown in Scheme 4 below (Nettekoven M. et al., Synthesis 2003, 11,1649-1652). In a typical procedure, 2-aminopyridine compounds of Formula(VI) whereby R₁, R₂, R₃, and R₄ are as above defined are reacted with analkyloxycarbonylisothiocyanate of Formula (IX) where R₁₄ is an alkylgroup such as methyl or ethyl in an appropriate solvent such as dioxaneto give thiourea compounds (VII). Cyclisation of thiourea compounds(VII) to triazolopyridine amines of Formula (II) is then performed inpresence of hydroxylamine or hydroxylamine hydrochloride in conjunctionwith an appropriate base such diisopropylethylamine and in anappropriate solvent such as methanol and ethanol.

According to a further general process, compounds of Formula (II) can beconverted to alternative compounds of Formula (II), employing suitableinterconversion techniques well known by a person skilled in the art.

A preferred method as of scheme 5 to prepare the triazolopyridine aminecompounds of Formula (IIa) whereby R₂, R₃, R₄ and NR₆R₇ are as abovedefined, consists in reacting triazolopyridine amine compounds accordingto the general Formula (IIb) whereby R₂, R₃ and R₄ are as above definedand R¹ is F, Cl, Br, I, OMs, OTf or SR₁₃ where R₁₃ is an alkyl groupwith an amine R₆R₇NH (V). In a typical procedure, triazolopyridine aminecompounds according to the general Formula (IIb) and amines R₆R₇NH (V)are heated at various temperature by traditional thermic methods orusing microwave technology in an appropriate solvent such as ethanol,butanol or the amine itself such as those described hereafter in theexamples.

2-aminopyridine compounds of Formula (VI) whereby R¹, R², R³, and R⁴ areas above defined may be obtained either from commercial sources or theymay be prepared from known compounds using procedures such as thosedescribed hereinafter in the examples, or conventional procedures, knownby one skilled in the art.

A preferred method as of scheme 6 to prepare 2-amino pyridine compounds(VIa) whereby one of R¹, R², R³ and R⁴, as above defined, is an aryl, aheteroaryl or an alkenyl group R′¹, consist in reacting 2-aminopyridinecompounds (VIb) whereby one of R′, R², R³ and R⁴, as above defined, is agroup X selected from a halogen atom such as Cl, Br, I or a sulfonateester such as OTf with a boronic acid (IVa) or ester (IVb) whereby R′¹is as above defined using well known Suzuki-Miyaura reaction conditions(Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Takahiro I. andToshiaki M., Tetrahedron Lett. 2005, 46, 3573-3577). In a typicalprocedure, 2-aminopyridine compounds of Formula (VIb) and boronic acid(IVa) or ester (IVb) are heated at various temperature by traditionalthermic methods or using microwave technology in presence of a base suchas K₂CO₃, K₃PO₄ or CsF and a catalytic amount of palladium catalyst suchas PdCl₂(PPh₃)₂ or Pd(OAc)₂ with DPPF in an appropriate solvent such asDMF or a combination of water with THF or dioxane such as thosedescribed hereinafter in the Examples.

If the above set of general synthetic methods is not applicable toobtain compounds according to Formula (I) and/or necessary intermediatesfor the synthesis of compounds of Formula (I), suitable methods ofpreparation known by a person skilled in the art should be used.

Compounds of this invention can be isolated in association with solventmolecules by crystallization or from evaporation of an appropriatesolvent. The pharmaceutically acceptable acid addition salts of thecompounds of Formula (I), which contain a basic center, may be preparedin a conventional manner. For example, a solution of the free base maybe treated with a suitable acid, either neat or in a suitable solution,and the resulting salt isolated either by filtration or by evaporationunder vacuum of the reaction solvent.

The pharmaceutically acceptable cationic salts of compounds of thepresent invention are readily prepared by reacting the acid forms withan appropriate base, usually one equivalent, in a co-solvent. Typicalbases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodiumhydride, potassium hydroxide, potassium methoxide, magnesium hydroxide,calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine,meglumine, benethamine, diethylamine, piperazine and tromethamine. Thesalt is isolated by concentration to dryness or by addition of anon-solvent. In some cases, salts can be prepared by mixing a solutionof the acid with a solution of the cation (sodium ethylhexanoate,magnesium oleate), employing a solvent in which the desired cationicsalt precipitates, or can be otherwise isolated by concentration andaddition of a non-solvent.

The compounds of invention have been named according the standards usedin the program “ACD/Name Batch” from Advanced Chemistry DevelopmentInc., ACD/Labs (7.00 Release). Product version: 7.10, build: 15 Sep.2003.

EXAMPLES

The novel compounds according to Formula (I) can be prepared fromreadily available starting materials by several synthetic approaches,using both solution-phase and solid-phase chemistry protocols or mixedsolution and solid phase protocols. Examples of synthetic pathways forthe will be described.

The commercially available starting materials used in the followingexperimental description were purchased from Aldrich, Fluka or Acrosunless otherwise reported.

The HPLC, NMR and MS data provided in the examples described below areobtained as followed: HPLC: Waters Alliance 2695 equipped with WatersX-Bridge column C8 50×4.6 mm 3.5 μm, Conditions: MeCN (0.05% TFA)/H2O(0.1% TFA), 5 to 100% (8 min), max plot 230-400 nm; LC/MS spectra:waters ZMD (ES) equipped with Waters X-Bridge column C8 30×2.1 mm 3.5μm; ¹H-NMR: Bruker DPX-300 MHz unless otherwise reported.

The preparative HPLC purifications are performed with a mass directedautopurification Fractionlynx from Waters equipped with a sunfire prepC18 OBD column 19×100 mm 5 μm, unless otherwise reported. All HPLCpurifications were performed with a gradient of ACN/H₂O or ACN/H₂O/HCOOH(0.1%).

The microwave chemistry is performed on a single mode microwave reactorEmrys™ Optimiser from Personal Chemistry.

INTERMEDIATES Intermediate A

Intermediate A1: 5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine Stepa) Formation of 6-(3-thienyl)pyridin-2-amine

To a mixture of 2-amino-6-bromopyridine (Lancaster, 5.0 g; 28.9 mmol;1.0 eq.), 3-thienylboronic acid (4.44 g; 34.7 mmol; 1.2 eq.), potassiumphosphate (12.27 g; 57.8 mmol; 2.0 eq.) in dry dioxane (150 mL) wasadded 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (1.06 g;1.44 mmol; 0.05 eq.) under inert atmosphere. The reaction mixture washeated at 80° C. overnight, cooled down to rt, filtered on a bed ofcelite and filtrates were evaporated under reduced pressure.Purification of the crude by flash chromatography on silica (gradientEtOAc/c-Hex, 5:95 to 50:50) gave the title compound as a beige solid(3.71 g, 73%). HPLC, Rt: 1.51 min. (purity 96.4%). LC/MS, M⁺(ESI):177.4.

Step b) Formation ofethyl({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate

A solution of 6-(3-thienyl)pyridin-2-amine (3.70 g; 21.0 mmol; 1.0 eq.)and ethoxycarbonyl isothiocyanate (2.73 mL; 24.1 mmol; 1.15 eq.) indioxane (100 mL) was stirred at rt overnight. The precipitate formed wasfiltered and washed with c-Hex to give the title compound as a whitesolid (4.73 g; 73%). HPLC, Rt: 4.26 min. (purity 99.9%). LC/MS, M⁺(ESI):308.3.

Step c) Formation of 5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A1

A suspension ofethyl({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate (4.0 g;13.01 mmol; 1.0 eq.), hydroxylamine hydrochloride (4.52 g; 65.1 mmol;5.0 eq.) and DIEA (6.55 mL) in MeOH/EtOH (1:1, 120 mL) was stirred at rtfor 2 hours and then at 70° C. for 3 hours. Solvents were removed underreduced pressure, the residue was taken up in dioxane/water (1:1) andfiltered to give the title compound as a white powder (2.3 g; 82%).HPLC, Rt: 1.75 min. (purity 94.8%). LC/MS, M⁺(ESI): 217.3.

Intermediate A2: 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine Stepa) Formation of 6-(3-furyl)pyridin-2-amine

The title compound was prepared following procedure described forintermediate A1 step a), but starting from 2-amino-6-chloropyridine(25.0 g; 194.5 mmol; 1.0 eq.) and furan-3-boronic acid (26.11 g; 233.4mmol; 1.2 eq.). The crude was purified by flash chromatography(EtOAc/c-Hex, 50:50) to give the title compound as a brown oil (16.91 g;54%). ¹H NMR (DMSO-d₆) δ 7.96 (s, 1H), 7.42 (m, 2H), 6.82 (m, 2H), 6.37(d, J=7.2 Hz, 1H), 4.54 (m, 2H). HPLC, Rt: 1.30 min. (purity 84.9%).LC/MS, M⁺(ESI): 161.4.

Step b) Formation ofethyl({[6-(3-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 6-(3-furyl)pyridin-2-amine(16.0 g; 105.5 mmol; 1.0 eq.) as a white solid (28.2 g; 92%). HPLC, Rt:3.98 min. (purity 99.7%). LC/MS, M⁺(ESI): 292.3, M⁻(ESI): 290.2.

Step c) Formation of 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A2

The title compound was prepared following procedure described forintermediate A1 step c), but starting fromethyl({[6-(3-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate (28.1 g;96.5 mmol; 1.0 eq.) as a clear beige powder (17.26 g; 89%). ¹H NMR(DMSO-d₆) (δ 8.92 (s, 1H), 7.88 (d, J=1.7 Hz, 1H), 7.50 (t, J=8.1 Hz,1H), 7.29-7.37 (m, 3H), 6.11 (s, 2H). HPLC, Rt: 1.59 min. (purity99.6%). LC/MS, M⁺(ESI): 201.3.

Intermediate A3: 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine Step a)Formation of ethyl {[(6-bromopyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 2-amino-6-bromopyridine (20.0g; 115.6 mmol; 1.0 eq.) as a white solid (36 g, quant. yield). HPLC, Rt:4.17 min. (purity 99.8%). LC/MS, M⁺(ESI): 306.1.

Step b) Formation of 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A3

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(6-bromopyridin-2-yl)amino]carbonothioyl}carbamate (36.0 g; 118.4mmol; 1.0 eq.) as a yellowish solid (20.65 g; 82%). HPLC, Rt: 1.03 min.(purity 97.6%). LC/MS, M⁺(ESI): 215.2.

Intermediate A4: 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine Step a)formation of ethyl {[(6-chloropyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 2-amino-6-chloropyridine(49.38 g; 384.1 mmol; 1.0 eq.) as a yellow solid (107 g, quant. yield).HPLC, Rt: 3.93 min. (purity 94.5%). LC/MS, M⁺(ESI): 260.0.

Step b) formation of 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A4

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(6-chloropyridin-2-yl)amino]carbonothioyl}carbamate (99.76 g; 384.1mmol; 1.0 eq.) as a greenish solid (51.19 g; 79.0%). HPLC, Rt: 0.92 min.(purity 98.1%). LC/MS, M⁺(ESI): 169.0.

Intermediate A5: 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine Step a)Formation of ethyl {[(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 2-amino-5-bromopyridine (35.0g; 202.3 mmol; 1.0 eq.) as a yellowish solid (60 g; 97%). HPLC, Rt: 4.04min. (purity 92.4%). LC/MS, M⁺(ESI): 305.9.

Step b) Formation of 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A5

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate (61.0 g; 200.6mmol; 1.0 eq.) as an off white powder (42.6 g; 99%). HPLC, Rt: 1.18 min.(purity 97.3%). LC/MS, M⁺(ESI): 214.9.

Intermediate A6: tert-butyl2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylateStep a) Formation of tert-butyl2-(6-aminopyridin-2-yl)-1H-pyrrole-1-carboxylate

The title compound was prepared following procedure described forintermediate A1 step a), but starting from 2-amino-6-chloropyridine(2.05 g; 16.0 mmol; 1.0 eq.) and ethyl1-(t-butoxycarbonyl)pyrrole-2-boronic acid (5.06 g; 24.0 mmol; 1.5 eq.)as a beige powder (1.15 g, 27%). HPLC, Rt: 2.65 min. (purity 97.0%).LC/MS, M⁺(ESI): 204.3.

Step b) Formation of tert-butyl2-[6-({[(ethoxycarbonyl)amino]carbonothioyl}amino)pyridin-2-yl]-1H-pyrrole-1-carboxylate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from tert-butyl2-(6-aminopyridin-2-yl)-1H-pyrrole-1-carboxylate (1.15 g; 4.43 mmol; 1.0eq.) as a beige solid (1.47 g, 85%). HPLC, Rt: 4.99 min. (purity 94.0%).LC/MS, M⁺(ESI): 335.2.

Step c) Formation of tert-butyl2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate

Intermediate A6

The title compound was prepared following procedure described forintermediate A1 step c), but starting from tert-butyl2-[6-({[(ethoxycarbonyl)amino]carbonothioyl}amino)pyridin-2-yl]-1H-pyrrole-1-carboxylate(1.47 g; 3.76 mmol; 1.0 eq.) as a beige solid (870 mg, 77%). HPLC, Rt:2.68 min. (purity 98.5%). LC/MS, M⁺(ESI): 244.3.

Intermediate A7:5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine Stepa) Formation of 6-chloro-4-(trifluoromethyl)pyridin-2-amine

A solution of 2,6-dichloro-4-(trifluoromethylpyridine) (Fluorochem, 10.0g; 46.30 mmol; 1.0 eq.) in ammonium hydroxide (˜25% in water) (40.0 mL;4.0 V) was heated to 180° C. for 3 h in a Parr apparatus and cooled downto rt. After this time, reaction mixture was filtered over a bed ofcelite, evaporated to dryness under reduced pressure, triturated withDCM and filtered. The mother liquors were concentrated under reducedpressure to give the title compound as a yellow oil that crystallizedupon standing (4.83 g; 53%). HPLC, Rt: 3.58 min. (purity 96.9%). LC/MS,M⁺(ESI): 196.8, M⁻(ESI): 194.8.

Step b) formation ofethyl({[6-chloro-4-(trifluoromethyl)pyridin-2-yl]amino}carbonothioyl)carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from6-chloro-4-(trifluoromethyl)pyridin-2-amine (4.83 g; 24.57 mmol; 1.0eq.) as a beige solid (6.90 g; 86%). HPLC, Rt: 5.00 min. (purity 96.0%).LC/MS, M⁺(ESI): 327.9.

Step c) Formation of5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A7

The title compound was prepared following procedure described forintermediate A1 step c), but starting fromethyl({[6-chloro-4-(trifluoromethyl)pyridin-2-yl]amino}carbonothioyl)carbamate(6.90 g; 21.1 mmol; 1.0 eq.) as a white powder (3.6 g, 72%). HPLC, Rt:2.45 min. (purity 98.9%). LC/MS, M⁺(ESI): 236.8, M⁻(ESI): 234.8.

Intermediate A8: 6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amineStep a) Formation of ethyl{[(5-bromo-6-methylpyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from6-amino-3-bromo-2-methylpyridine (25.0 g; 133.7 mmol; 1.0 eq.) as ayellow powder (41.80 g; 98%). HPLC, Rt: 4.49 min. (purity 99.3%). LC/MS,M⁺(ESI): 319.9, M⁻(ESI): 317.9.

Step b) Formation of6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A8

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(5-bromo-6-methylpyridin-2-yl)amino]carbonothioyl}carbamate (41.8 g;131.4 mmol; 1.0 eq.) as a white solid (23.90 g; 80%). HPLC, Rt: 1.55min. (purity 99.9%). LC/MS, M⁺(ESI): 228.9.

Intermediate A9: N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine

Intermediate A9

A suspension of 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4),10.0 g; 59.32 mmol; 1.0 eq.) in cyclohexylamine (60 mL) was heated toreflux for 52 h. Reaction mixture was taken up in MTBE and filtered. Theresulting cake was washed with MTBE and filtrate was concentrated todryness. Residue was purified by flash chromatography (Hept/EtOAc, 1:1)to give the title compound as a beige powder (8.08 g, 59%). HPLC, Rt:2.46 min. (purity 98.9%). LC/MS, M⁺(ESI): 231.9.

Intermediate A10:N⁵-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine

Intermediate A10

The title compound was prepared following procedure described forintermediate A9, but starting from5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 2.88 g; 17.1 mmol;1.0 eq.) and cycloheptylamine (14 mL) and heated at 180° C. for 1 hunder microwave radiation to give the title compound as a beige oil(2.48 g; 59%). HPLC, Rt: 2.90 min. (purity 97.2%). LC/MS, M⁺(ESI):292.9.

Intermediate A11: 5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A11

Cyclohexanol (1.68 mL; 15.84 mmol; 5.0 eq.) was added to a suspension ofNaH (152 mg; 3.80 mmol; 1.2 eq.) in THF (6.0 mL) and maintained underinert atmosphere at 0° C. The reaction mixture was brought back to rtand stirred for 1 h before the addition of5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 534 mg; 3.17 mmol;1.0 eq.). Reaction mixture was then heated at reflux for 3 h after whichtime it was quenched by addition of water. It was then extracted withEtOAc, washed with brine, dried over magnesium sulfate, filtered andconcentrated. Purification by flash chromatography on silica gel(DCM/MeOH, 95:5 to 10:90) gave the title compound as a white solid (590mg, 80%). HPLC, Rt: 2.18 min. (purity 90.1%). LC/MS, M⁺(ESI): 233.0.

Intermediate A12:5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A12

5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3); 1.06 g; 5.0 mmol;1.0 eq.), pyrazole (3.40 g; 50.0 mmol; 10 eq.) and potassium hydroxide(842 mg; 15.0 mmol; 3.0 eq.) were melted and stirred overnight at 110°C. After this time, reaction mixture was cooled to rt poured into waterand extracted with Et₂O. The combined organic layers were washed withwater, dried over magnesium sulfate, filtered and evaporated underreduced pressure to give the title compound as a white solid (650 mg,65%). HPLC, Rt: 1.22 min. (purity 96.6%). LC/MS, M⁺(ESI): 201.0.

Intermediate A13: [1,2,4]triazolo[1,5-a]quinolin-2-amine Step a)Formation of ethyl[(quinolin-2-ylamino)carbonothioyl]arbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from quinolin-2-amine (1.06 g;7.35 mmol; 1.0 eq.) as a yellow powder (1.68 g, 83%). HPLC, Rt: 3.66min. (purity 97.8%). LC/MS, M⁻(ESI): 274.3.

Step b) Formation of [1,2,4]triazolo[1,5-c]quinolin-2-amine

Intermediate A13

The title compound was prepared following procedure described forintermediate A1 step c), but starting fromethyl[(quinolin-2-ylamino)carbonothioyl]carbamate (1.68 g; 6.10 mmol;1.0 eq.) as a white powder (667 mg, 59%). ¹H NMR (DMSO-d₆) δ 8.26 (d,J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.70 (m,1H), 7.47 (m, 1H), 7.45 (d, J=9.0 Hz, 1H). HPLC, Rt: 1.62 min. (purity99.7%). LC/MS, M⁺(ESI): 185.4.

Intermediate A14:6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine Step a)Formation of 5-bromo-6-chloropyridin-2-amine

N-bromosuccinimide (16.45 g; 92.41 mmol; 1.10 eq.) was added portionwiseto a solution of 2-amino-6-chloropyridine (10.80 g; 84.01 mmol; 1.0 eq.)in DMF (200 mL) at rt. The reaction mixture was stirred at rt for 2hours. Solvents were removed under reduced pressure and the residue wastaken up in EtOAc and aqueous ammonia. The organic phase was washedagain with aqueous ammonia and brine, dried over magnesium sulfate,filtered and concentrated under reduced pressure. The black solidobtained was washed with pentane and dried under vacuum to give thetitle compound as a beige powder (12.5 g, 72%). HPLC, Rt: 2.81 min.(purity 95.8%).

Step b) Formation of ethyl{[(5-bromo-6-chloropyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from5-bromo-6-chloropyridin-2-amine (7.09 g; 34.2 mmol; 1.0 eq.) as anoff-white solid (8.80 g; 76%). HPLC, Rt: 4.65 min. (purity 100.0%).

Step c) Formation of6-bromo-5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(5-bromo-6-chloropyridin-2-yl)amino]carbonothioyl}carbamate (8.80 g;26.0 mmol; 1.0 eq.) as a beige powder (4.56 g; 70%). HPLC, Rt: 1.96 min.(purity 91.5%). LC/MS, M⁺(ESI): 248.8.

Step d) Formation of6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine

Intermediate A14

The title compound was prepared following procedure described forintermediate A9 but starting from6-bromo-5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.0 g; 12.1 mmol;1.0 eq.) and cyclohexylamine (12.0 mL; 104.9 mmol; 8.65 eq.) to give thetitle compound as a dark foam (2.5 g, 66%). HPLC, Rt: 3.21 min. (purity76.6%). LC/MS, M⁺(ESI): 310.0.

Intermediate A15:6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine Step a)Formation of ethyl {[(3-bromopyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1, step b) but starting from 2-amino-3-bromopyridine (4.18g; 24.16 mmol; 1.0 eq.) to give the title compound as a light yellowishpowder (7.4 g, quant. yield). HPLC, Rt: 2.72 min. (purity 99.7%). LC/MS,M⁺(ESI): 303.9.

Step b) Formation of 8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A15

The title compound was prepared following procedure described forintermediate A1, step c) but starting from ethyl{[(3-bromopyridin-2-yl)amino]carbonothioyl}carbamate (7.40 g; 24.33mmol; 1.0 eq.) to give the title compound as a white solid (4.4 g, 85%).HPLC, Rt: 1.16 min. (purity 99.8%). LC/MS, M⁺(ESI): 212.9, 214.9.

Intermediate A16: 5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine Stepa) Formation of 6-(2-furyl)pyridin-2-amine

The title compound was prepared following procedure described forintermediate A1 step a), but starting from 2-amino-6-chloropyridine(925.64 mg; 7.20 mmol; 1.0 eq.) and 2-furanboronic acid (1.21 g; 10.8mmol; 1.5 eq.). The crude was purified by flash chromatography(EtOAc/c-Hex, gradient from 25:75 to 40:60) to give the title compound(990 mg; 86%). HPLC, Rt: 1.33 min. (purity 99.9%). LC/MS, M⁺(ESI):161.0.

Step b) Formation ofethyl({[6-(2-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 6-(2-furyl)pyridin-2-amine(970 mg; 6.06 mmol; 1.0 eq.) as a white solid (1.67 g; 94%). HPLC, Rt:4.07 min. (purity 98.4%). LC/MS, M⁺(ESI): 292.0, M⁻(ESI): 290.1.

Step c) Formation of 5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A16

The title compound was prepared following procedure described forintermediate A1 step c), but starting fromethyl({[6-(2-furyl)pyridin-2-yl]amino}carbonothioyl)carbamate (1.65 g;5.66 mmol; 1.0 eq.) as a white powder (1.13 g; 99%). HPLC, Rt:1.75 min.(purity 98.4%). LC/MS, M⁺(ESI): 201.1.

Intermediate A17:N⁵-isopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine

Intermediate A17

A suspension of5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7),183.00 mg; 0.77 mmol; 1.00 eq.) and isopropylamine (664.58 μl; 7.74mmol; 10.00 eq.) in n-butanol (1.50 mL) was heated at 120° C. for 1 h 30under MW irradiation. The reaction mixture was then concentrated undervacuum till dryness. The solid obtained was triturated in water/MTBE andfiltered. The solid which precipitated in mother liquor was finallyfiltered, washed with water and dried under vacuum at 40° C. to give thetitle compound as an off-white solid (122 mg, 61%). HPLC, Rt: 2.64 min.(purity 86.5%). LC/MS, M⁺(ESI): 259.9, M⁻(ESI): 257.9.

Intermediate A18:N⁵-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine

Intermediate A18

A suspension of5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7),3.60 g; 15.22 mmol; 1.0 eq.), cyclopropylamine (5.27 mL; 76.1 mmol; 5.0eq.), and N-ethyldiisopropylamine (26.22 mL; 152.2 mmol; 10. 0 eq.) washeated at 80° C. in 1-butanol (36.0 mL) for 23 h., then 15 h. at 100° C.The reaction mixture was then concentrated under vacuum till dryness.Diethyl ether was added and the solid was filtered, washed with waterand dried. The product was then purified by chromatography on silicagel(from 5% to 95% EtOAc in c-Hex), to give the title compound as a whitesolid (2.0 g; 51.1%). HPLC, Rt: 2.54 min. (purity 100%). LC/MS, M⁺(ESI):258.0, M⁻(ESI): 256.0.

Intermediate A19: 5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amineStep a) Formation of 6-Chloro-4-methylpyridin-2-amine

A solution of 2,6-Dichloro-4-methylpyridine (Chem. Mater., 2004, 16,1564-1572, 30 g, 0.185 mol) in ammonium hydroxide (200 mL, 25% solutionin water) was heated at 200° C. in a pressure vessel for 10 h. Thereaction mixture was then concentrated under reduced pressure. The brownsolid obtained was suspended in DCM for 30 min at 25-26° C. andfiltered. Filtrate was concentrated under reduced pressure. Purificationof the crude thus obtained by flash chromatography (20% ethyl acetate inpet ether) afforded the title compound as off-white solid (13.5 g, Yield51%). LC/MS: M⁺(ESI): 142.7; ¹H NMR (DMSO d₆: 400 MHz) δ 6.34 (1H, s),6.23 (2H, s), 6.15 (1H, s), 2.1 (3H, s).

Step b) Formation of ethyl{[(6-chloro-4-methylpyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 2-amino-4,6-dichloropyridine(2.5 g; 15.3 mmol; 1.0 eq.) as an off-white solid (5.0 g; 64%). HPLC,Rt: 4.36 min. (purity 98.3%). LC/MS, M⁺(ESI): 273.8, M⁻(ESI): 271.8.

Step c) Formation of5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine

Intermediate A19

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(6-chloro-4-methylpyridin-2-yl)amino]carbonothioyl}carbamate (5.0 g;18.4 mmol; 1.0 eq.) as a white solid (3.34 g; 99.5%). HPLC, Rt: 1.17min. (purity 92.8%). LC/MS, M⁺(ESI): 282.8.

Intermediate B

Intermediate B1: N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide

Intermediate B1

Benzoyl chloride (4.40 g; 31.4 mmol; 2.0 eq.) was added to a suspensionof 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3), 3.34 g; 15.7mmol; 1.0 eq.) in pyridine (2.53 mL; 31.4 mmol; 2.0 eq.) and DCM (60mL). The reaction mixture was then heated at reflux for 4 hours, afterwhich it was cooled down to rt. Diethyl ether was added to the reactionmixture and the solid which precipitated was filtered off. Theprecipitate was resuspended in an aqueous mixture (pH 4/5), filtered anddried under vacuum to give the title compound as a white powder (4.97 g,quant. yield). HPLC, Rt: 2.40 min. (purity 93.4%), LC/MS, M⁺(ESI):317.1, M⁻(ESI): 315.1.

Intermediate B2:N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

Intermediate B2

The title compound was prepared following procedure described forintermediate B1, but starting from5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3), 5.0 g; 23.5 mmol;1.0 eq.) and nicotinoyl chloride hydrochloride (8.36 g; 47.0 mmol; 2.0eq.) as a grey powder (5.86 g, 78%). HPLC, Rt: 1.24 min. (purity 97.4%).LC/MS, M⁺(ESI): 319.0, M⁻(ESI): 318.3.

Intermediate B3: N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide

Intermediate B3

The title compound was prepared following procedure described forintermediate B1, but starting from5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 84.29 mg; 0.50mmol; 1.0 eq.) and benzoyl chloride (70 mg; 0.50 mmol; 1.0 eq.) as awhite powder (136 mg, quant. yield). HPLC, Rt: 2.30 min. (purity 99.0%).LC/MS, M⁺(ESI): 273.0.

Intermediate B4:N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

Intermediate B4

The title compound was prepared following procedure described forintermediate B1, but starting from5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 14.60 g; 86.60mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (18.5 g; 1 μM mmol;1.2 eq.) as a greenish solid (20.61 g; 87%). HPLC, Rt: 1.19 min. (purity99.4%). LC/MS, M⁺(ESI): 274.3, M⁺(ESI): 272.3.

Intermediate B5: N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide

Intermediate B5

The title compound was prepared following procedure described forintermediate B1, but starting from6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A5), 5.0 g; 23.47 mmol;1.0 eq.) and benzoyl chloride (6.57 g; 46.9 mmol; 2.0 eq.) as a whitepowder (6.5 g, 87%). HPLC, Rt: 2.49 min. (purity 97.1%). LC/MS, M⁺(ESI):317.0, M⁻(ESI): 316.9.

Intermediate B6:N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide hydrochloride

Intermediate B6

The title compound was prepared following procedure described forintermediate B1, but starting from6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A5), 5.0 g; 23.5 mmol;1.0 eq.) and nicotinoyl chloride hydrochloride (5.01 g; 28.2 mmol; 1.2eq.) as a light yellow solid (6.30 g; 84%). HPLC, Rt: 1.32 min. (purity99.6%). LC/MS, M⁺(ESI): 317.9. CHN analysis: [C₁₂H₈N₅OBr.1.0HCl.1.0H₂O]Corrected: C 38.68%; H, 2.98%; N, 18.80%. Found: C, 38.76%; H, 3.11%; N,18.66%.

Intermediate B7:N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

Intermediate B7

The title compound was prepared following procedure described forintermediate B1, but starting from5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7),2.72 g; 11.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (2.46g; 13.8 mmol; 1.2 eq.) as a greenish solid (1.42 g; 36%). HPLC, Rt: 2.16min. (purity 100%). LC/MS, M⁺(ESI): 342.2, M⁻(ESI): 340.2.

Intermediate B8:4-(chloromethyl)-N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

Intermediate B8

The title compound was prepared following procedure described forintermediate B1, but starting fromN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 800 mg;3.46 mmol; 1.0 eq.) and 4-(chloromethyl)benzoyl chloride (981 mg; 5.2mmol; 1.5 eq.) as a brownish foam (1.32 g, 99%). LC/MS, M⁺(ESI): 384.0,M⁻(ESI): 382.0.

Intermediate B9: N-(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide

Intermediate B9

The title compound was prepared following procedure described forintermediate B1, but starting from8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A15), 4.40 g; 20.7 mmol;1.0 eq.) and benzoyl chloride (5.81 g; 41.3 mmol; 2.0 eq.) as a whitesolid (4.9 g, 74%). HPLC, Rt: 2.45 min. (purity 90.1%). LC/MS, M⁺(ESI):318.9, M⁻(ESI): 316.9.

Intermediate B10:N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide Step a)Formation of ethyl{[(4,6-dichloropyridin-2-yl)amino]carbonothioyl}carbamate

The title compound was prepared following procedure described forintermediate A1 step b), but starting from 2-amino-4,6-dichloropyridine(J&W Pharma, 2.50 g; 15.34 mmol; 1.00 eq.) as a white solid (4.27 g;94%). HPLC, Rt: 4.68 min. (purity 100%).

Step b) Formation of 5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-amine

The title compound was prepared following procedure described forintermediate A1 step c), but starting from ethyl{[(4,6-dichloropyridin-2-yl)amino]carbonothioyl}carbamate (4.27 g; 14.52mmol; 1.00 eq.) as a white solid (2.61 g; 88%). HPLC, Rt: 1.78 min(purity 97.9%). LC/MS, M⁺(ESI): 202.8.

Step c) Formation ofN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

Intermediate B10

The title compound was prepared following procedure described forintermediate B1, but starting from5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.00 g; 4.93 mmol;1.00 eq.) and nicotinoyl chloride hydrochloride (1 052.16 mg; 5.91 mmol;1.20 eq.) as a yellowish solid (1.06 g, 70%). HPLC, Rt 1.61 min. (purity92.4%). LC/MS, M⁺(ESI): 307.7, M⁻(ESI): 305.8.

Intermediate B11:6-chloro-N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

Intermediate (B11)

To a reaction vessel containingN-5-cyclohexyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine (500 mg, 2.16mmol, 1 eq.) and triethylamine (0.75 mL, 5.40 mmol, 2.5 eq.) inacetonitrile (8 mL) was added 6-chloronicotinyl chloride (952 mg, 5.40mmol, 2.5 eq.) in acetonitrile (2 mL), dropwise. The vessel was cappedand stirred at room temperature for 16 hours. The solvent was removed invacuo and the resulting solid dissolved in methanolic ammonia (15 mL, 7N) and stirred at room temperature for a further 24 hours. The solventwas removed in vacuo and the solid dissolved in ethyl acetate (40 mL).The organic phase was washed with water (3×20 mL), dried (MgSO₄) andconcentrated. The resulting solid was triturated with dichloromethaneand filtered to give the title compound as a white solid (250 mg, 31%).No further purification carried out.

Intermediate B12:N-(5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

Intermediate B12

The title compound was prepared following procedure described forintermediate B1, but starting from5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine (282 mg; 1.54mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (330 mg; 1.85 mmol;1.20 eq.) as a off-white powder (244 mg, 55%). HPLC, Rt: 1.51 min.(purity 90.4%). LC/MS, M⁺(ESI): 288.1, M⁻(ESI): 286.2.

Example 1N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-phenylacetamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 41 mg; 0.20mmol; 1.0 eq.) and phenylacetyl chloride (38 μl; 0.41 mmol; 2.0 eq).Purification of the compound by flash chromatography on silica(EtOAc/c-Hex, 50:50) gave the title compound as a white powder (21 mg,29%). ¹H NMR (DMSO-d₆) δ 8.98 (brs, 1H), 8.61 (brs, 1H), 7.55 (m, 3H),7.37 (m, 5H), 7.22 (m, 1H), 6.91 (s, 1H), 3.96 (brs, 2H), 1.99 (brs, 3H,water). HPLC, Rt: 3.27 min. (purity 94.5%). LC/MS, M⁺(ESI): 319.3,M⁻(ESI): 317.3.

Example 2 N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

A solution of nicotinic acid (74 mg, 0.6 mmol, 1.2 eq.) and1,1-carbonyldiimidazole (122 mg, 0.75 mmol, 1.5 eq.) in dry THF (1 mL)was stirred for 45 min. at rt. In parallel, a solution of5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50mmol; 1.0 eq.) and sodium tert-butoxide (96 mg, 1.0 mmol, 2.0 eq.) indry THF (2 mL) was stirred for 45 min. at rt. The two solutions werethen combined and the reaction mixture was stirred overnight at rt. Et₂Owas then added and the precipitate obtained was filtered, washed withEt₂O, THF, a 5N solution of NaOH and water. It was resuspended in anacidic aqueous solution (pH 1) and filtered to give the title compoundas a white powder (52.4 mg, 31%). HPLC, Rt: 1.98 min. (purity 95.1%).LC/MS, M⁺(ESI): 306.1, M⁻(ESI): 304.1.

Example 3N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(trifluoromethyl)benzamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30mmol; 1.0 eq.) and 4-(trifluoromethyl)benzoyl chloride (125 mg, 0.60mmol; 2.0 eq.) as a white powder (31.2 mg, 28%). HPLC, Rt: 4.02 min.(purity 99.4%). LC/MS, M⁺(ESI): 373.2, M⁻(ESI): 373.1.

Example 4 Ethyl3-{[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropanoate

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30mmol; 1.0 eq.) and ethyl 3-chloro-3-oxopropionate (90 mg, 0.60 mmol; 2.0eq.) as a white powder (42 mg, 45%). HPLC, Rt: 2.72 min. (purity 90.8%).LC/MS, M⁺(ESI): 315.3, M⁻(ESI): 313.3.

Example 5N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-methoxyacetamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30mmol; 1.0 eq.) and methoxyacetyl chloride (65 mg, 0.60 mmol; 2.0 eq.) asa white powder (59 mg, 72%). HPLC, Rt: 2.21 min. (purity 98.2%). LC/MS,M⁺(ESI): 273.4, M⁻(ESI): 271.4.

Example 66-chloro-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30mmol; 1.0 eq.) and 6-chloronicotinoyl chloride (65 mg, 0.60 mmol; 2.0eq.) as a white powder (47.7 mg, 47%). HPLC, Rt: 3.00 min. (purity98.6%). LC/MS, M⁺(ESI): 340.2, M⁻(ESI): 338.2.

Example 7 Methyl4-{[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-4-oxobutanoate

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30mmol; 1.0 eq.) and 3-carbomethoxypropionyl chloride (65 mg, 0.60 mmol;2.0 eq.) as a white powder (83.5 mg, 88%). HPLC, Rt: 2.40 min. (purity95.4%). LC/MS, M⁻(ESI): 313.2.

Example 82-(benzyloxy)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]acetamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30mmol; 1.0 eq.) and phenoxyacetyl chloride (65 mg, 0.60 mmol; 2.0 eq.) asa white powder (61.3 mg, 58%). HPLC, Rt: 3.59 min. (purity 96.1%).LC/MS, M⁺(ESI): 349.3, M⁻(ESI): 347.3.

Example 93-methoxy-N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forintermediate B1, but starting from tert-butyl2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate((A6), 50 mg; 0.17 mmol; 1.0 eq.) and m-anisoyl chloride (57 mg; 0.33mmol; 2.0 eq.). Further treatment with a DCM/TFA solution (2:1) andpurification by flash chromatography on silica (EtOAc/c-Hex, gradientfrom 50:60 to 80:20) gave the title compound as a white solid (23.1 mg,41%). HPLC, Rt: 3.40 min. (purity 94.7%). LC/MS, M⁺(ESI): 334.3,M⁻(ESI): 332.3.

Example 10N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentanecarboxamide

The title compound was prepared following procedure and work updescribed for example 9, but starting from tert-butyl2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate((A6), 50 mg; 0.17 mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (44mg; 0.33 mmol; 2.0 eq.) as a white solid (25.4 mg, 51%). HPLC, Rt: 3.17min. (purity 99.7%). LC/MS, M⁺(ESI): 296.4, M⁻(ESI): 294.3.

Example 11N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure and work updescribed for example 9, but starting from tert-butyl2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate((A6), 50 mg; 0.17 mmol; 1.0 eq.) and benzoyl chloride (47 mg; 0.33mmol; 2.0 eq.) as a white solid (22.7 mg, 45%). HPLC, Rt: 3.23 min.(purity 91.6%). LC/MS, M⁺(ESI): 304.3, M⁻(ESI): 302.3.

Example 12N-[5-(1H-pyrazol-4-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B1), 75 mg;0.24 mmol; 1.0 eq.) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (139 mg; 0.47 mmol; 2.0 eq.), at 140° C. for 14 h.Further treatment with a 1 N methanolic HCl solution (0.5 mL) andpurification by flash chromatography on silica (EtOAc/c-Hex, 80:20) gavethe title compound as a white powder (23 mg, 32%). HPLC, Rt: 2.07 min.(purity 96.9%). LC/MS, M⁺(ESI): 305.3, M⁻(ESI): 303.3.

Example 13N-[5-(1H-pyrrol-2-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 9, but starting from tert-butyl2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate((A6), 360 mg; 1.20 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride(428 mg; 2.41 mmol; 2.0 eq.) as a brown powder (245 mg, 67%). HPLC, Rt:2.14 min. (purity 100.0%). LC/MS, M⁻(ESI): 303.3.

Example 14 N-[5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B1), 75 mg;0.24 mmol; 1.0 eq.) and 2-furanboronic acid (53 mg; 0.47 mmol; 2.0 eq.).

Purification by flash chromatography on silica (EtOAc/c-Hex, 45:55) gavethe title compound as an off-white powder (19 mg, 26%). HPLC, Rt: 3.24min. (purity 97.9%). LC/MS, M⁺(ESI): 305.3, M⁻(ESI): 303.2.

Example 15N-[6-(3-fluorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and 3-fluorophenylboronic acid (66 mg; 0.47 mmol;2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc,5:95) gave the title compound as a beige powder (42 mg, 53%). HPLC, Rt:2.40 min. (purity 99.7%). LC/MS, M⁺(ESI): 334.3, M⁻(ESI): 332.3.

Example 16 N-(6-phenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl) nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and phenylboronic acid (57 mg; 0.47 mmol; 2.0 eq.).Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gavethe title compound as a beige powder (42 mg, 56%). HPLC, Rt: 2.26 min.(purity 98.7%).

Example 17 N-[6-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and furan-3-boronic acid (57 mg; 0.47 mmol; 2.0eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95)gave the title compound as a beige powder (15.6 mg, 21%). HPLC, Rt: 1.82min. (purity 92.2%). LC/MS, M⁺(ESI): 306.3, M⁻(ESI): 304.3.

Example 18N-[6-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and 3-thienylboronic acid (60 mg; 0.47 mmol; 2.0eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95)gave the title compound as a beige powder (18.1 mg, 23%). HPLC, Rt: 2.13min. (purity 94.3%). LC/MS, M⁺(ESI): 322.3, M⁻(ESI): 320.2.

Example 19N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-methoxybenzamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and m-anisoyl chloride (85 mg; 0.50 mmol; 2.0 eq.). Crudewas purified on SPE NH₂ column and the title compound was isolated as awhite powder (26.9 mg, 32%). HPLC, Rt: 3.32 min. (purity 89.0%). LC/MS,M⁺(ESI): 306.4.

Example 20N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-(2-thienyl)acetamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 2-thiopheneacetyl chloride (80 mg; 0.50 mmol; 2.0eq.) as a white powder (30.9 mg, 38%). HPLC, Rt: 3.28 min. (purity96.6%). LC/MS, M⁺(ESI): 357.2, M⁻(ESI): 355.2.

Example 21N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentanecarboxamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (66 mg; 0.50 mmol; 2.0eq.) as a white powder (64.1 mg, 86%). HPLC, Rt: 3.11 min. (purity82.7%). LC/MS, M⁺(ESI): 297.4, M⁻(ESI): 295.3.

Example 22N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-methoxybenzamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and p-anisoyl chloride (66 mg; 0.50 mmol; 2.0 eq.) as awhite powder (58.2 mg, 69%). HPLC, Rt: 3.19 min. (purity 97.0%).

Example 23N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]isonicotinamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and isonicotinoyl chloride hydrochloride (89 mg; 0.50mmol; 2.0 eq.) as a white powder (39.4 mg, 51%). HPLC, Rt: 1.90 min.(purity 97.2%). LC/MS, M⁺(ESI): 306.4, M⁻(ESI): 304.4.

Example 24N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]quinoxaline-6-carboxamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 6-quinoxalinecarbonyl chloride (96 mg; 0.50 mmol; 2.0eq.) as a white powder (47.5 mg, 53%). HPLC, Rt: 2.73 min. (purity62.3%). LC/MS, M⁺(ESI): 357.4, M⁻(ESI): 355.3.

Example 25N-[6-(3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and 3-methoxybenzeneboronic acid (71 mg; 0.47 mmol;2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM,gradient from 0:100 to 10:90) gave the title compound as a beige powder(43 mg, 53%). HPLC, Rt: 2.41 min. (purity 99.2%). LC/MS, M⁺(ESI): 346.4,M⁻(ESI): 344.4.

Example 26N-[6-(3-aminophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a) but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and 3-aminobenzeneboronic acid (64 mg; 0.47 mmol;2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM,gradient from 0:100 to 10:90) gave the title compound as a dark redsolid (31 mg, 40%). HPLC, Rt: 1.07 min. (purity 96.3%). LC/MS, M⁺(ESI):331.4, M⁻(ESI): 329.4.

Example 27N-[6-(3-cyanophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate A1 step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg;0.24 mmol; 1.0 eq.) and 3-cyanophenylboronic acid (69 mg; 0.47 mmol; 2.0eq.). Purification by flash chromatography on silica (MeOH/DCM, gradientfrom 0:100 to 10:90) gave the title compound as a brown powder (6 mg,7%). HPLC, Rt: 2.09 min. (purity 92.5%). LC/MS, M⁺(ESI): 341.4.

Example 28N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]isoxazole-5-carboxamide

The title compound was prepared following procedure described forexample 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and isoxazole-5-carbonyl chloride (49 mg; 0.37 mmol; 1.5eq.) as a white powder (19.4 mg, 26%). HPLC, Rt: 2.62 min. (purity95.3%). LC/MS, M⁺(ESI): 296.4, M⁻(ESI): 294.3.

Example 29N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (74mg; 0.37 mmol; 1.5 eq.) as a white powder (34 mg, 37%). HPLC, Rt: 3.17min. (purity 81.5%). LC/MS, M⁺(ESI): 363.0.

Example 30N-[5-(cyclopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg;0.16 mmol; 1.0 eq.) in cyclopropylamine (1 mL) was heated at 80° C.overnight. The reaction mixture was diluted with H₂O and extracted withEtOAc. Combined organic phases were washed with brine, dried overmagnesium sulfate, filtered and concentrated. The title compound wasobtained by recrystallization in EtOAc/c-Hex as a white powder (16.60mg; 35%). HPLC, Rt: 1.77 min. (purity 98.3%). LC/MS, M⁺(ESI): 295.4,M⁻(ESI): 293.4.

Example 31 N-(5-pyrrolidin-1-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

The title compound was prepared following procedure and work updescribed for example 30, but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg;0.16 mmol; 1.0 eq.) and pyrrolidine (1 mL) as a white solid (1 mg, 2%).HPLC, Rt: 1.81 min. (purity 97.3%). LC/MS, M⁺(ESI): 309.4, M⁻(ESI):307.4.

Example 32N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3,5-dimethoxybenzamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 3,5-dimethoxybenzoyl chloride (60 mg; 0.30 mmol; 1.2eq.) as a white powder (42.9 mg; 47%). HPLC, Rt: 3.51 min. (purity95.3%). LC/MS, M⁺(ESI): 365.3, M⁻(ESI): 363.3.

Example 33N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]biphenyl-4-carboxamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 4-biphenylcarbonyl chloride (87 mg; 0.37 mmol; 1.5eq.) as a white powder (53.7 mg, 56%). HPLC, Rt: 4.25 min. (purity95.2%). LC/MS, M⁺(ESI): 381.4, M⁻(ESI): 379.4.

Example 341-(4-chlorophenyl)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentanecarboxamide

The title compound was prepared following procedure described forintermediate B1, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 1-(4-chlorophenyl)-1-cyclopentanecarbonyl chloride(Lancaster, 91 mg; 0.37 mmol; 1.5 eq.) as a white foam (61.1 mg, 60%).HPLC, Rt: 4.64 min. (purity 73.4%). LC/MS, M⁺(ESI): 407.4, M⁻(ESI):405.4.

Example 35N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,3-dihydro-1-benzofuran-5-carboxamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 2,3-dihydro-1-benzofuran-5-carbonyl chloride (68 mg;0.37 mmol; 1.5 eq.) as a white solid (25.7 mg, 29%). HPLC, Rt: 3.14 min.(purity 78.8%). LC/MS, M⁺(ESI): 347.4, M⁻(ESI): 345.3.

Example 36 N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-furamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 3-furoyl chloride (39 mg; 0.3 mmol; 1.2 eq.) as awhite powder (45.3 mg, 61%). HPLC, Rt: 2.65 min. (purity 97.5%). LC/MS,M⁺(ESI): 295.4, M⁻(ESI): 293.4.

Example 371-acetyl-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]piperidine-4-carboxamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 1-acetylpiperidine-4-carbonyl chloride (57 mg; 0.3mmol; 1.2 eq.) as a white powder (41.3 mg, 46%). HPLC, Rt: 2.15 min.(purity 93.3%). LC/MS, M⁺(ESI): 354.4, M⁻(ESI): 352.4.

Example 382,2-Difluoro-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1,3-benzodioxole-4-carboxamide

The title compound was prepared following procedure and work updescribed for example 19, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride(Alpha, 66 mg; 0.3 mmol; 1.2 eq.) as a white powder (75.2 mg, 78%).HPLC, Rt: 4.01 min. (purity 97.4%). LC/MS, M⁺(ESI): 385.3, M⁻(ESI):383.3.

Example 39N-[5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 2, but starting from5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A1), 82 mg; 0.38mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (55 mg; 0.3 mmol;1.2 eq.) as a beige solid (21 mg, 26%). HPLC, Rt: 2.15 min. (purity97.3%). LC/MS, M⁺(ESI): 322.0, M⁻(ESI): 320.0.

Example 40 N-[1,2,4]triazolo[1,5-a]quinolin-2-ylnicotinamide

The title compound was prepared following procedure described forexample 2, but starting from [1,2,4]triazolo[1,5-a]quinolin-2-amine((A13), 67 mg; 0.37 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride(80 mg; 0.44 mmol; 1.2 eq.). Purification by flash chromatography onsilica (DCM/MeOH, gradient from 98:2 to 95:5) gave the title compound asan orange oil (27 mg, 38%). HPLC, Rt: 1.83 min. (purity 97.9%). LC/MS,M⁺(ESI): 290.0, M⁻(ESI): 288.0.

Example 41N-[5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forexample 30, but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 44 mg;0.16 mmol; 1.0 eq.) and cyclopentylamine (1.0 mL) as a white powder (23mg, 44%). HPLC, Rt: 3.06 min. (purity 99.5%). LC/MS, M⁺(ESI): 322.1,M⁻(ESI): 320.1.

Example 42 N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide1-oxide

The title compound was prepared following procedure described forexample 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50mmol; 1.0 eq.) and nicotinic acid N-oxide (83 mg, 0.6 mmol, 1.2 eq.) asa light yellow solid (37.2 mg, 23%). HPLC, Rt: 1.98 min. (purity 98.8%).LC/MS, M⁺(ESI): 322.1, M⁻(ESI): 320.1.

Example 43N-{5-[(3-methoxypropyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following ToN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5) fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg;0.18 mmol; 1.0 eq.) and 3-methoxypropylamine (195 μl; 1.91 mmol; 10.0eq.) in THF (3.0 mL), 90° C., 12 h, as white needles (35 mg; 56%). HPLC,Rt: 1.95 min. (purity 99.3%). LC/MS, M⁺(ESI): 326.2.

Example 44N-{5-[(2-furylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg;0.18 mmol; 1.0 eq.) and furfurylamine (1.0 mL) as a beige powder (31 mg,51%). HPLC, Rt: 2.20 min. (purity 94.1%). LC/MS, M⁺(ESI): 334.1,M⁻(ESI): 332.1.

Example 45N-{5-[(tetrahydrofuran-2-ylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg;0.18 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a whitepowder (32 mg, 52%). HPLC, Rt: 2.34 min. (purity 91.7%). LC/MS, M⁺(ESI):339.0, M⁻(ESI): 338.1.

Example 463-(Acetylamino)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forexample 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50mmol; 1.0 eq.) and isophthalamic acid (49 mg, 0.3 mmol, 1.2 eq.) as abeige powder (20 mg, 23%). HPLC, Rt: 2.64 min. (purity 90.7%). LC/MS,M⁺(ESI): 362.1, M⁻(ESI): 360.1.

Example 47N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg;0.18 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as an off-white powder(50 mg, 81%). HPLC, Rt: 3.33 min. (purity 94.3%). LC/MS, M⁺(ESI): 336.2,M⁻(ESI): 334.1.

Example 48N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-(methylsulfonyl)benzamide

The title compound was prepared following procedure described forexample 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and 3-methylsulphonylbenzoic acid (60 mg, 0.3 mmol, 1.2eq.) as an off-white solid (9 mg, 9%). HPLC, Rt: 2.79 min. (purity96.5%). LC/MS, M⁺(ESI): 383.0, M⁻(ESI): 381.0.

Example 493-(aminomethyl)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamideStep a) Formation oftert-butyl[3-({[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)benzyl]carbamate

The title compound was prepared following procedure and work updescribed for example 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25mmol; 1.0 eq.) and boc-(3-aminomethyl)-benzoic acid (75 mg; 0.3 mmol;1.2 eq.) as a white solid 20.0 mg, 18%). HPLC, Rt: 3.86 min. (purity75.6%). LC/MS, M⁺(ESI): 434.1, M⁻(ESI): 432.2.

Step b) Preparation of3-(aminomethyl)-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

Tert-butyl[4-({[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)benzyl]carbamate(20 mg, 0.05 mmol, 1.0 eq.) was suspended in DCM/TFA (50:1, 1 mL) andreaction mixture was stirred at rt for 1 h. The reaction mixture wasthen concentrated under vacuum, the residue slurried with diethyl etherand filtered to give the title compound as a white solid (11 mg, 54%).HPLC, Rt: 3.57 min. (purity 96.3%). LC/MS, M⁺(ESI): 334.1.

Example 50N-(5-{[1-(hydroxymethyl)propyl]amino}[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide

The title compound was prepared following procedure described forexample 30, but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 52 mg;0.19 mmol; 1.0 eq.) and 2-amino-1-butanol (0.2 mL) as a white powder (13mg, 22%). HPLC, Rt: 2.25 min. (purity 90.7%). LC/MS, M⁺(ESI): 326.2.

Example 51N-[6-(3-hydroxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forintermediate A1, step a), but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 75 mg;0.24 mmol; 1.0 eq.) and 3-hydroxyphenylboronic acid (65 mg; 0.47 mmol;2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex,gradient from 50:50 to 100:0) gave the title compound as a brown solid(9.5 mg, 12%). HPLC, Rt: 2.59 min. (purity 91.6%). LC/MS, M⁺(ESI):331.1, M⁻(ESI): 329.1.

Example 52tert-butyl[4-({[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)benzyl]carbamate

The title compound was prepared following procedure and work updescribed for example 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37mmol; 1.0 eq.) and boc-(4-aminomethyl)-benzoic acid (113 mg; 0.45 mmol;1.2 eq.) as a white foam (35.4 mg, 22%). HPLC, Rt: 3.69 min. (purity88.9%). LC/MS, M⁺(ESI): 434.1, M⁻(ESI): 432.1.

Example 53N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-isobutylbenzamide

The title compound was prepared following procedure and work updescribed for example 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37mmol; 1.0 eq.) and 4-isobutylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) asa yellow foam (25.5 mg, 19%). HPLC, Rt: 4.39 min. (purity 93.6%). LC/MS,M⁺(ESI): 361.1, M⁻(ESI): 359.1.

Example 54Tert-butyl[4-({[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)phenoxy]acetate

The title compound was prepared following procedure and work updescribed for example 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37mmol; 1.0 eq.) and 4-(2-t-butoxy-2-oxoethoxy)benzoic acid (113 mg; 0.45mmol; 1.2 eq.) as a white foam (21.6 mg, 13%). HPLC, Rt: 3.98 min.(purity 98.3%). LC/MS, M⁺(ESI): 435.1, M⁻(ESI): 433.1.

Example 55 4-butyl-N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure and work updescribed for example 2, but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37mmol; 1.0 eq.) and 4-butylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as ayellow foam (20 mg, 15%). HPLC, Rt: 4.45 min. (purity 82.6%). LC/MS,M⁺(ESI): 361.1, M⁻(ESI): 359.1.

Example 56N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamidehydrochloride

To N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 400 mg;1.26 mmol; 1.0 eq.), cesium fluoride (383 mg; 2.52 mmol; 2.0 eq.)dichlorobis(triphenylphosphine)palladium (89 mg; 0.13 mmol; 0.10 eq.)and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (631mg; 2.52 mmol; 2.0 eq.) in a sealed tube, under inert atmosphere, wereadded dioxane (3.2 mL) and water (1.6 mL). The mixture was heated at120° C. for 12 hours. The reaction mixture was cooled down to rt andfiltered over a celite pad. The celite was carefully rinsed with MeOHand a 0.1N solution of HCl was added to the filtrate. The desiredproduct was precipitated by addition of EtOAc, filtered and dried underreduced pressure as a beige solid (373 mg, 74%). ¹H NMR (DMSO-d₆) δ11.27 (s, 1H), 9.24 (s, 1H), 8.03-8.01 (m, 3H), 7.76 (d, J=9 Hz, 1H),7.65-7.51 (m, 3H), 7.37 (d, J=1.8 Hz, 1H), 7.22 (dd, J=1.8, 8.2 Hz, 1H),6.89 (d, J=8.2 Hz, 1H), 4.7-3.9 (bs, 7H), 3.89 (s, 3H). HPLC, Rt: 2.59min. (purity 96.4%). LC/MS, M⁺(ESI): 361.03, M⁻(ESI): 359.05. CHNanalysis: [C₂₀H₁₆N₄O₃.1.0HCl.2.0H₂O] Corrected: C 55.50%; H, 4.89%; N,12.94%. Found: C, 55.83%; H, 4.84%; N, 13.14%.

Example 57N-{5-[(2-methoxyethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg;0.18 mmol; 1.0 eq.) and 2-methoxyethylamine (1.0 mL) as an off-whitesolid (52 mg, 91%). HPLC, Rt: 2.08 min. (purity 90.1%). LC/MS, M⁺(ESI):312.1, M⁻(ESI): 310.1.

Example 58N-{5-[(2,3-dihydroxypropyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg;0.18 mmol; 1.0 eq.) and 3-amino-1,2-propanediol (1.0 mL) as a whitepowder (6 mg, 7%). HPLC, Rt: 1.65 min. (purity 99.5%). LC/MS, M⁺(ESI):328.1, M⁻(ESI): 326.1.

Example 59N-[6-(2,3-dihydro-1-benzofuran-5-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forexample 56 but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 150 mg;0.47 mmol; 1.0 eq.) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (155mg; 0.95 mmol; 2.0 eq.). Purification by flash chromatography on silica(EtOAc/c-Hex, gradient from 40:60 to 100:0) gave the title compound as awhite solid (117.2 mg, 69%). HPLC, Rt: 3.18 min. (purity 84.6%). LC/MS,M⁺(ESI): 357.1, M⁻(ESI): 355.1.

Example 60N-[5-(benzylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg;0.31 mmol; 1.0 eq.) and benzylamine (1.0 mL) as an oily solid (10 mg,9%). HPLC, Rt: 2.46 min. (purity 85.8%). LC/MS, M⁺(ESI): 345.1, M⁻(ESI):343.1.

Example 61N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamidedihydrochloride

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 296mg; 1.08 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL). The parentcompound was dissolved in MeOH and Et₂O/HCl was added. The precipitateobtained was filtered, washed with Et₂O and dried under reduced pressureat 40° C. to give the title compound as a white powder (178 mg, 42%).HPLC, Rt: 2.98 min. (purity 99.7%). LC/MS, M⁺(ESI): 351.4, M⁻(ESI):349.4. CHN analysis: [C₁₉H₂₂N₆O.2.0HCl.1.5H₂O] Corrected: C 50.67%; H,6.04%; N, 18.66%. Found: C, 50.69%; H, 5.97%; N, 18.61%.

Example 62N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg;0.31 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as a white powder (37mg, 42%). HPLC, Rt: 2.60 min. (purity 99.6%). LC/MS, M⁺(ESI): 337.1,M⁻(ESI): 335.2.

Example 63N-(5-{[(5-methyl-2-furyl)methyl]amino}[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg;0.31 mmol; 1.0 eq.) and 5-methylfurfurylamine (1.0 mL) as an off-whitesolid (40 mg, 37%). HPLC, 2.38 min. Rt: (purity 98.6%). LC/MS, M⁻(ESI):347.1.

Example 64N-{5-[(tetrahydrofuran-2-ylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg;0.31 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a whitepowder (17 mg, 16%). HPLC, Rt: 1.73 min. (purity 95.5%). LC/MS, M⁺(ESI):339.1, M⁻(ESI): 337.1.

Example 65N-[6-(4-hydroxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forexample 56 but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 150 mg;0.47 mmol; 1.0 eq.) and 4-hydroxyphenylboronic acid (131 mg; 0.95 mmol;2.0 eq.) as a white solid (15 mg, 9%). HPLC, Rt: 2.60 min. (purity97.2%). LC/MS, M⁺(ESI): 331.1, M⁻(ESI): 329.1.

Example 66N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamidehydrochloride

The title compound was prepared following procedure described forexample 56 but starting fromN-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 400 mg;1.26 mmol; 1.0 eq.) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (629 mg;2.51 mmol; 2.0 eq.) as a light yellow solid (249 mg, 55%). HPLC, Rt:1.71 min. (purity 60.7%). LC/MS, M⁺(ESI): 362.0, M⁻(ESI): 360.0. CHNanalysis: [C₁₉H₁₅N₅O₃.1HCl.0.4CH₃CN.0.6H₂O] Corrected: C 55.95%; H,4.36%; N, 17.79%. Found: C, 55.95%; H, 4.76%, N, 17.53%.

Example 67N-[5-(cyclooctylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 58 mg;0.21 mmol; 1.0 eq.) and cyclooctylamine (440 μL) as a white powder (4mg, 4%). HPLC, Rt: 3.25 min. (purity 97.9%). LC/MS, M⁺(ESI): 365.4,M⁻(ESI): 363.4.

Example 68N-{5-[cyclohexyl(methyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 55 mg;0.20 mmol; 1.0 eq.) and N-methylcyclohexylamine (1.0 mL) as an off whitesolid (30 mg, 43%). HPLC, Rt: 2.67 min. (purity 97.8%). LC/MS, M⁺(ESI):351.4, M⁻(ESI): 349.4.

Example 69N-[5-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg;0.31 mmol; 1.0 eq.) and 4-aminotetrahydropyran (Apollo), 1.0 mL) as awhite powder (15 mg, 14%). ¹H NMR (DMSO-d₆) δ 11.27 (s, 1H), 9.13 (d,J=1.9 Hz, 1H), 8.77 (d, J=4.9, 1.5 Hz, 1H), 8.33 (dd, J=8.0, 1.9 Hz,1H), 7.58 (m, 1H), 7.51 (t, J=8.5 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.62(d, J=8.7 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 3.88 (m, 2H), 3.80 (m, 1H),3.45 (m, 2H), 1.89 (m, 2H), 1.72 (m, 2H). HPLC, Rt: 1.51 min. (purity99.0%). LC/MS, M⁺(ESI): 339.4, M⁻(ESI): 337.4.

Example 70N-{5-[(1-methylpiperidin-4-yl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg;0.31 mmol; 1.0 eq.) and 4-amino-1-methyl-piperidine (1.0 mL) as a whitepowder (30 mg, 27%). ¹H NMR (DMSO-d₆) δ 11.25 (brs, 1H), 9.13 (d, J=1.9Hz, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.32 (dd, J=8.0, 2.0 Hz, 1H),7.56 (dd, J=8.1, 4.7 Hz, 1H), 7.51 (t, J=8.3 Hz, 1H), 6.89 (d, J=7.9 Hz,1H), 6.46 (d, J=8.3 Hz, 1H), 6.312 (d, J=7.5 Hz, 1H), 3.49 (m, 1H), 2.77(m, 2H), 2.17 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.70 (m, 2H). HPLC,Rt: 1.07 min. (purity 100.0%). LC/MS, M⁺(ESI): 352.4, M⁻(ESI): 350.4.

Example 71N-{5-[(3-aminocyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following procedure described forexample 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 52 mg;0.19 mmol; 1.0 eq) and 1,3-cyclohexanediamine (1.0 mL). The crude wasdirectly purified by preparative HPLC (Starting with 45% ACN in waterfor 5 min, then up to 60% in 10 min.). The title compound was isolatedafter lyophilisation as a white powder (63 mg, 94%). HPLC, Rt: 1.84 min.(purity 98.2%). LC/MS, M⁺(ESI): 351.4, M⁻(ESI): 349.4.

Example 72N-{5-[(1-methylpiperidin-4-yl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide

The title compound was prepared following procedure and work updescribed for example 71 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 100 mg;0.37 mmol; 1.0 eq.) and 4-amino-1-methyl-piperidine (ABCR, 0.50 mL) as awhite powder (59 mg, 46%). ¹H NMR (DMSO-d₆) δ 10.91 (brs, 1H), 8.00 (d,J=7.2 Hz, 2H), 7.57 (m, 4H), 6.87 (d, J=8.3 Hz, 1H), 6.49 (d, J=8.3 Hz,1H), 6.29 (d, J=7.9 Hz, 1H), 3.84 (m, 1H), 2.74 (m, 2H), 2.16 (s, 3H),2.03 (m, 2H), 1.92 (m, 2H), 1.66 (m, 2H). HPLC, Rt: 1.70 min. (purity99.4%). LC/MS, M⁺(ESI): 351.4, M⁻(ESI). 349.4.

Example 73N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 71 but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclopropylamine (1.0 mL) as awhite powder (30 mg, 59%). HPLC, Rt: 2.98 min. (purity 99.6%). LC/MS,M⁺(ESI): 363.3, M⁻(ESI): 361.3.

Example 74N-[5-(cyclohexylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 71 at rt but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as awhite powder (3 mg, 5%). HPLC, Rt: 3.78 min. (purity 100%). LC/MS,M⁺(ESI): 405.3, M⁻(ESI): 403.2.

Example 75N-[5-(cycloheptylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 71 at rt but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL) as awhite powder (8 mg, 13%). HPLC, Rt: 3.85 min. (purity 95.9%). LC/MS,M⁺(ESI): 419.3, M⁻(ESI): 417.4.

Example 76N-[5-(cyclopentylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq.) in cyclopentylamine (1.0 mL) wasstirred at rt overnight. The reaction mixture was diluted with asaturated solution of NaHCO₃ (10 mL) and EtOAc (5 mL). The two phaseswere separated and the organic phase was washed four times with asaturated solution of NaHCO₃, after which the product precipitated inthe organic phase. It was filtered, washed with a saturated solution ofNaHCO₃ and EtOAc, dried under vacuum and isolated as a white solid (13mg, 23%). HPLC, Rt: 3.54 min. (purity 100%). LC/MS, M⁺(ESI): 391.3,M⁻(ESI): 389.3.

Example 77N-[5-[(cyclohexylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 76 but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexanemethylamine (500 μl) asa white powder (27 mg; 44%). HPLC, Rt: 4.11 min. (purity 99.8%). LC/MS,M⁺(ESI): 419.4, M⁻(ESI): 417.4.

Example 78 N-(6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide

The title compound was prepared following procedure described forintermediate B1, but starting from6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A8), 4.0 g;17.62 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (3.76 g; 21.1mmol; 1.2 eq.) as a yellow solid (4.53 g; 77%). ¹H NMR (DMSO-d₆) δ 11.54(s, 1H), 9.13 (d, J=2.3 Hz, 1H), 9.78 (dd, J=4.9, 1.5 Hz, 1H), 8.34 (dt,J=7.9, 1.8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.63-7.54 (m, 2H), 2.8 (s,3H). HPLC, Rt: 1.75 min. (purity 98.8%). LC/MS, M⁺(ESI): 334.2. CHNanalysis: [C₁₃H₁₀N₅OBr.1.0H₂O] Corrected: C 44.59%; H, 3.45%; N, 20.00%.Found: C, 44.68%; H, 3.41%; N, 19.97%.

Example 79N-{5-[(3-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

3-amino-cyclohexanol (Betapharma, 67.33 mg; 0.58 mmol; 2.0 eq.) wasadded to a mixture ofN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg;0.29 mmol; 1.0 eq.), DIEA (76 mg; 0.58 mmol; 2.0 eq.) and activatedCharcoal (8 mg) in tBuOH (0.8 mL). The reaction mixture was heated at200° C. for 2×30 min under microwave irradiation. After this time, itwas filtered on a celite pad and the cake was washed with ACN. Thefiltrate was directly purified by RP-HPLC (Starting with 15% ACN inwater for 5 min, then up to 30% in 10 min.). The title compound wasisolated after lyophilisation as a white powder (51 mg, 49%). HPLC, Rt:2.14 min. (purity 98.0%). LC/MS, M⁺(ESI): 353.0, M⁻(ESI): 351.0.

Example 80N-{5-[(4-tert-butylcyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

The title compound was prepared following procedure and work updescribed for example 79 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg;0.29 mmol; 1.0 eq.) and 4-tert-butylcyclohexylamine (91 mg; 0.58 mmol;2.0 eq.) as a white powder (32 mg, 27%). HPLC, Rt: 4.63 min. (purity99.3%). LC/MS, M⁺(ESI): 393.1, M⁻(ESI): 391.1.

Example 81N-[5-(tetrahydro-2H-pyran-3-ylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure and work updescribed for example 30 but starting fromN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 100 mg;0.37 mmol; 1.0 eq.) and tetrahydro-pyran-3-ylamine hydrochloride (CBI,257 mg; 1.87 mmol; 5 eq.) in DMA (1 mL) as a white powder (32 mg, 26%).¹H NMR (DMSO-d₆) (δ 11.05 (s, 1H), 8.00 (d, J=6.8 Hz, 2H), 7.48-7.63 (m,4H), 6.91 (d, J=8.3 Hz, 1H), 6.46 (d, J=9.0 Hz, 1H), 6.36 (d, J=7.9 Hz,1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.50 (m, 2H), 2.06 (m, 1H), 1.22-1.97(m, 3H). HPLC, Rt: 2.27 min. (purity 99.6%). LC/MS, M⁺(ESI): 338.1,M⁻(ESI): 336.0.

Example 82N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(morpholin-4-ylmethyl)benzamide

The title compound was prepared following procedure described forintermediate B1, but starting fromN⁵-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A10), 123 mg;0.50 mmol; 1.0 eq.) and 4-(chloromethyl)benzoyl chloride (142 mg; 0.75mmol; 1.5 eq.). Solvents were removed under reduced pressure to yield agummy solid that was resuspended in morpholine (1.74 g; 20.0 mmol; 10.0eq.) and the mixture was stirred at 60° C. for 2 h. After this time,reaction mixture was cooled down to rt, solvents were evaporated underreduced pressure and the residue washed with Et₂O (4×5 mL). A solidcrystallized in the Et₂O phase which, after filtration, gave the titlecompound as a white solid (90 mg, 40%). HPLC, Rt: 3.99 min. (purity98.9%). LC/MS, M⁺(ESI): 423.1, M⁻(ESI): 421.1.

Example 83N-[5-(cyclohexylthio)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

To a solution ofN-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 136mg; 0.5 mmol; 1.0 eq.) in dry THF (10 mL) was added in one potcyclohexyl mercaptan (58 mg; 0.5 mmol; 1.0 eq.). The reaction mixturewas stirred at rt for 14 h. The product precipitated upon addition ofwater after which filtration and washing with MeOH and Et₂O gave thetitle compound as a white solid (78 mg, 44%). HPLC, Rt: 2.94 min.(purity 94.6%). LC/MS, M⁺(ESI): 354.1, M⁻(ESI): 352.0.

Example 84N-{5-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

A solution of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide((B4), 100 mg; 0.37 mmol; 1.0 eq.), trans-4-aminocyclohexanolhydrochloride (ABCR), 277 mg; 1.83 mmol; 5.0 eq.), DIEA (472 mg; 3.65mmol; 10.0 eq.) in n-butanol (1.0 mL) was heated at 220° C. for 20 minunder microwave irradiation. The reaction mixture was directly purifiedby reverse phase chromatography (Starting with water then up to 60% ACNin water in 40 min.). The title compound was isolated afterlyophilisation as a white powder (31 mg, 24%). HPLC, Rt: 1.77 min.(purity 80.2%). LC/MS, M⁺(ESI): 353.1, M⁻(ESI): 351.1.

Example 85N-[5-(cyclobutylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 84, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 100 mg; 0.3 mmol; 1.0 eq.) and cyclobutylamine (125 μl; 0.150mmol; 5.0 eq.) at 120° C. for 30 min. under microwave irradiations.Solvents were removed under vacuum to dryness after which the residuewas triturated with water, filtered and washed with EtOAc to give thetitle compound as a white powder (59 mg; 53%). ¹H NMR (DMSO-d₆) δ 11.4(s, 1H), 9.15 (d, J=2.2 Hz, 1H), 8.79 (dd, J=1.5, 4.5 Hz, 1H), 8.35 (dt,J=1.8, 7.9 Hz, 1H), 7.63-7.56 (m, 2H), 7.32 (bs, 1H), 6.36 (d, J=1.5 Hz,1H), 4.32-4.24 (m, 1H), 2.43-2.34 (m, 2H), 2.25-2.18 (m, 2H), 1.79-1.70(m, 2H). HPLC, Rt: 3.20 min. (purity 94.8%). LC/MS, M⁺(ESI): 377.0,M⁻(ESI): 375.0.

Example 86N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide

The title compound was prepared following procedure described forintermediate B1, but starting fromN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 174 mg;0.75 mmol; 1.0 eq.) and 6-morpholinonicotinoyl chloride (255 mg; 1.12mmol; 1.5 eq.) as a white solid (15 mg, 5%). HPLC, Rt: 2.83 min. (purity99.0%). LC/MS, M⁺(ESI): 422.2, M⁻(ESI): 420.1.

Example 87N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(dimethylamino)methyl]benzamide

The title compound was prepared following procedure described forexample 82, but starting fromN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((B8), 288 mg;0.75 mmol; 1.0 eq.) and dimethylamine (2 mL, 2M solution in THF) as ayellow powder (91 mg, 31%). HPLC, Rt: 2.65 min. (purity 97.4%). LC/MS,M⁺(ESI): 393.1, M⁻(ESI): 391.1.

Example 88N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-(morpholin-4-ylmethyl)benzamide

The title compound was prepared following procedure described forexample 82, but starting fromN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((B8), 173 mg;0.75 mmol; 1.0 eq.) and morpholine (653 mg, 7.5 mmol, 10 eq.) as an offwhite powder (120 mg, 37%). HPLC, Rt: 2.69 min. (purity 99.3%). LC/MS,M⁺(ESI): 435.2, M⁻(ESI): 433.1.

Example 89N-[5-[(cyclopropylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 85, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.15 mmol; 1.0 eq.) and (aminomethyl)cyclopropane (52 μl;0.73 mmol; 5.0 eq.) as a white solid (43 mg, 78%). HPLC, Rt: 3.19 min.(purity 78.6%). LC/MS, M⁺(ESI): 420.0, M⁻(ESI): 418.0.

Example 90 Methyltrans-4-{[2-[(pyridin-3-ylcarbonyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-5-yl]amino}cyclohexanecarboxylate

The title compound was prepared following procedure described forexample 85, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.15 mmol; 1.0 eq.) and trans-4-amino-cyclohexylcarboxylicacid methyl ester hydrochloride (IRIS), 52 μl; 0.73 mmol; 5.0 eq.) as awhite powder (23 mg, 34%). HPLC, Rt: 3.33 min. (purity 96.4%). LC/MS,M⁺(ESI): 463.1, M⁻(ESI): 461.1.

Example 91N-[5-{[(1RS,2RS)-2-(hydroxymethyl)cyclohexyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 85, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.15 mmol; 1.0 eq.) andtrans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (121 mg; 0.73mmol; 5.0 eq.) as a white solid (32 mg, 50%). HPLC, Rt: 3.00 min.(purity 89.6%). LC/MS, M⁺(ESI): 435.1, M⁻(ESI): 433.0.

Example 92N-[6-bromo-5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forintermediate B1, but starting from6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A14),616 mg; 1.99 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (424mg; 2.38 mmol; 1.2 eq.) as a beige powder (99 mg, 12%). HPLC, Rt: 3.41min. (purity 94.6%). LC/MS, M⁺(ESI): 416.9.

Example 93N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide

The title compound was prepared following procedure described forintermediate B1, but starting fromN⁵-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A10), 50 mg;0.20 mmol; 1.0 eq.) and tetrahydro-2H-pyran-4-carbonyl chloride (45 mg;0.30 mmol; 1.5 eq.) as a white solid (33 mg, 46%). HPLC, Rt: 3.02 min.(purity 96.9%). LC/MS, M⁺(ESI): 358.0, M⁻(ESI): 356.0.

Example 94N-[5-(2-methylprop-1-en-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamidedihydrochloride

N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 141.00mg; 0.52 mmol; 1.00 eq.), 2,2-dimethylethenylboronic acid (Synthonix,102.96 mg; 1.03 mmol; 2.00 eq.), cesium fluoride (156.53 mg; 1.03 mmol;2.00 eq.) and bis(triphenylphosphine)palladium(II) chloride (36.16 mg;0.05 mmol; 0.10 eq.) were flushed with nitrogen in a sealed vial. THF(degassed with nitrogen, 1.50 mL) and water (1 mL) were then added andthe mixture was heated at 120° C., O/N in an oil bath. A solution ofsaturated NH₄Cl was added and the reaction mixture was extracted withEtOAc (twice). Combined Organic phases were washed with brine, driedover magnesium sulfate, filtered and concentrated to give 186 mg of ayellow foam. Hydrochloride salt was then obtained by addition ofEt₂O/HCl (1 M solution) to a solution of this crude in DCM. Theprecipitate obtained was filtered and dried under vacuum at 40° C. togive the title compound as a beige solid (181 mg, 96%). HPLC, Rt: 2.05min. (purity 92.3%). LC/MS, M⁺(ESI): 293.9, M⁻(ESI): 291.9.

Example 95N-(3-oxo-3-{[5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}propyl)benzamide

The title compound was prepared following procedure and work updescribed for example 94 but starting from5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A12), 43 mg;0.27 mmol; 1.0 eq.) as a white solid (13 mg, 13%). HPLC, Rt: 2.41 min.(purity 87.3%). LC/MS, M⁺(ESI): 376.0, M⁻(ESI): 374.0.

Example 96N-(3-{[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide

The title compound was prepared following procedure and work updescribed for example 94 but starting from5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 43 mg; 0.27mmol; 1.0 eq.) as a white solid (52 mg, 51%). HPLC, Rt: 2.72 min.(purity 84.8%). LC/MS, M⁺(ESI): 376.0, M⁻(ESI): 374.0.

Example 97N-(3-{[5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide

The title compound was prepared following procedure and work updescribed for example 94 but starting from5-(2-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A16), 43 mg; 0.27mmol; 1.0 eq.) as a white solid (51 mg, 42%). HPLC, Rt: 2.85 min.(purity 92.7%). LC/MS, M⁺(ESI): 447.0, M⁻(ESI): 445.0.

Example 98N-(3-{[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide

The title compound was prepared following procedure and work updescribed for example 94 but starting fromN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 49 mg;0.27 mmol; 1.0 eq.) as a white solid (28 mg, 25%). HPLC, Rt: 3.22 min.(purity 87.4%). LC/MS, M⁺(ESI): 407.1, M⁻(ESI): 405.0.

Example 99N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 85 but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.15 mmol; 1.0 eq.) and isopropylamine (43 mg, 0.73 mmol;5.0 eq.) as a white solid (8 mg, 15%). HPLC, Rt: 3.09 min. (purity87.7%). LC/MS, M⁺(ESI): 365.0, M⁻(ESI): 363.0.

Example 100N-[5-(sec-butylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 85 but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.15 mmol; 1.0 eq.) and sec-butylamine (53.50 mg; 0.73mmol; 5.0 eq.) as a white solid (4 mg, 7%). HPLC, Rt: 3.44 min. (purity89.4%). LC/MS, M⁺(ESI): 379.1, M⁻(ESI): 377.0.

Example 101N-[5-(methylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 85 but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.15 mmol; 1.0 eq.) and methylamine (1.46 mL of a 2Msolution in MeOH; 0.73 mmol; 5.0 eq.) as a white solid (15 mg, 30%).HPLC, Rt: 2.47 min. (purity 96.6%). LC/MS, M⁺(ESI): 337.0, M⁻(ESI):335.0.

Example 102 N-[8-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure and work updescribed for example 56 but starting fromN-(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B9), 159 mg;0.50 mmol; 1.0 eq.) and furan-3-boronic acid (112 mg; 1.0 mmol; 2.0 eq.)as a white powder (80 mg, 52%). HPLC, Rt: 3.26 min. (purity 99.6%).LC/MS, M⁺(ESI): 305.0, M⁻(ESI): 303.1.

Example 103N-[5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-(3-methoxyphenyl)acetamide

The title compound was prepared following procedure and work updescribed for intermediate B1 but starting from5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A11), 80 mg;0.34 mmol; 1.0 eq.) and 3-methoxyphenylacetyl chloride (64 μl; 0.41mmol; 1.2 eq.) as a white powder (11 mg, 8%). HPLC, Rt: 3.60 min.(purity 88.2%). LC/MS, M⁺(ESI): 381.1, M⁻(ESI): 379.1.

Example 104N-[5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for intermediate B1 but starting from5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A11), 268 mg;1.15 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (247 mg; 1.38mmol; 1.2 eq.) as an off-white foam (230 mg, 59%). HPLC, Rt: 2.36 min.(purity 94.7%). LC/MS, M⁻(ESI): 336.1.

Example 105N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide

The title compound was prepared following procedure described forintermediate B1 but starting fromN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 116 mg;0.5 mmol; 1.0 eq.) and 6-(2-pyrrolidin-1-ylethyl)nicotinoyl chloride(239 mg, 1.0 mmol; 2.0 eq.) as a white powder (130 mg, 60%). HPLC, Rt:2.67 min. (purity 99.9%). LC/MS, M⁺(ESI): 434.1, M⁻(ESI): 432.1.

Example 106N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4-ylmethyl)nicotinamideStep a) Formation of potassium 6-(hydroxymethyl)pyridine-3-carboxylate

An aqueous solution of potassium hydroxide (40.4 mmol, 8 mL, 5 N, 2.0eq.) was added to a solution of ethyl6-(hydroxymethyl)pyridine-3-carboxylate (3.7 g; 20.4 mmol; 1.0 eq.) (J.Med. Chem. 2004, 47, 5230-5234) in THF (80 mL). The resulting reactionmixture was stirred at rt for 3 h. The precipitate was collected byfiltration and dried on under vacuum to give the title compound as awhite powder (3.6 g, 92%).

Step b) Formation of 6-(chloromethyl)pyridine-3-carbonyl chloridehydrochloride

To a suspension of potassium 6-(hydroxymethyl)pyridine-3-carboxylate (96mg; 0.50 mmol; 1.0 eq.) in DCM (1 mL) was added DMF (0.07 mg; 0.02 eq.,0.01 mmol). The mixture was chilled at 0° C. Then oxalyl chloride (317mg; 2.5 mmol; 5.0 eq.) was added dropwise and the resulting mixture wasstirred 4 h at rt. Evaporation of the solvent gave a black fine powderwithout further purification in the next step.

Step c) Formation ofN-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4-ylmethyl)nicotinamide

Pyridine (198 mg; 2.5 mmol; 5.0 eq.) was added to a solution ofN⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 116 mg;0.50 mmol; 1.0 eq.) in DCM (2.0 mL). 6-(chloromethyl)pyridine-3-carbonylchloride hydrochloride (190 mg; 1.0 mmol; 2.0 eq.) was added and theresulting black solution was stirred under reflux for 14 h. The solventswere evaporated to yield a black oil. Morpholine (218 mg; 2.5 mmol; 5.0eq.) and THF (0.5 mL) were added to this residue, and the mixture wasthen stirred and heated at 60° C. for 12 h. Purification by RP-HPLC(Waters Sunfire™ Prep C18 OBD™ 5 μM, 100×49 mm) following a gradientstarting with 20/80 (0.1% formic acid in CH₃CN/0.1% formic acid in H₂O)up to 95/5 in 12 min. The fractions were collected and lyophilized togive the title compound as a white powder (20 mg, 9%). HPLC, Rt: 2.11min. (purity 100%). LC/MS, M⁺(ESI): 436.3.

Example 107N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide

The title compound was acquired from Biofocus DPI (UK) cat. number:320_(—)4252_(—)0343.

Example 108 N-[5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was acquired from Biofocus DPI (UK) cat. Number:320_(—)4251_(—)0074.

Example 109 N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was acquired from Biofocus DPI (UK) cat. number:320_(—)4251_(—)0343.

Example 110 N-[5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was acquired from Biofocus DPI (UK), cat. number:320_(—)4262_(—)0343.

Example 111N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]acetamide

The title compound was acquired from Biofocus DPI (UK), cat. number:395_(—)2182_(—)0314.

Example 112N-[6-(4-hydroxy-3,5-dimethylphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 113 but using theN-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg,0.3 mmol, 1 mol eq.) and the2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (89mg, 0.36 mmol, 1.2 mol eq.) as a white solid (8.1 mg, 8%). HPLC, Rt:1.75 min (purity: 98%). LC/MS M+(ESI): 360.3.

Example 1134-[2-(benzoylamino)[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-[2-(dimethylamino)ethyl]benzamide

To a reaction vessel containingN-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg,0.3 mmol, 1 mol eq.), N-(2-dimethylamino-ethyl)-4-boronic acid-benzamide(85 mg, 0.36 mmol, 1.2 mol eq.) and cesium fluoride (135 mg, 0.9 mmol, 3mol eq.) in DMF (0.75 mL) and H₂O (0.5 mL) was addedbis-triphenylphosphine palladium dichloride (0.009 mmol, 3 mol %) in DMF(0.25 mL). The vessel was purged with nitrogen, capped and heated at 95°C. for approximately 18 hours. The reaction mixture was cooled to roomtemperature, filtered and the residue dissolved in DMSO (1.5 mL) andpurified by reverse phase preparatory HPLC to give the title compound asa white solid (30.4 mg, 24%). HPLC, Rt: 1.74 min (purity: 99%). LC/MSM⁺(ESI): 429.3, M⁻(ESI) 427.4.

Example 114N-[6-(1H-pyrazol-4-yl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure described forexample 112 but starting fromN-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg,0.3 mmol, 1 eq.) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Boron-Mol,85 mg, 0.36 mmol, 1.2 mol eq.) as a white solid (6.2 mg, 7%). HPLC, Rt:2.26 min (purity: 99%). LC/MS M⁺(ESI): 305.2.

Example 115N-{5-[(cyclohexylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide

To a microwave vial (0.5-2 mL) was addedN-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide (IntermediateB2, 60 mg, 0.19 mmol, 1 equivalent), diisopropylethylamine (0.05 mL,0.30 mmol, 1.5 equivalent), cyclohexyl-methylamine (34 mg, 0.3 mmol, 1.5equivalent) in butanol (0.6 mL). The mixture was heated in a Biotageinitiator 60 microwave at 220° C. for 30 minutes. The reaction mixturewas cooled and the solvent removed in vacuo. The residue dissolved inDMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give thetitle compound as a white solid (4.0 mg, 6%). HPLC, Rt: 2.56 min(purity: 99%). LC/MS M⁺(ESI): 351.2, M⁻(ESI) 349.2.

Example 116N-{5-[(4-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-methoxybenzamide

A sealed vessel containingN-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-methoxy-benzamide (69mg, 0.20 mmol, 1 mol eq.), trans-aminocyclohexanol (35 mg, 0.30 mmol,1.5 mol eq.), di-iso-propylethylamine (60 μL, 0.32 mmol, 1.6 mol eq.)and n-butanol (0.75 mL) was irradiated at 220° C., with stirring, for 20minutes. The solvent was removed in vacuo and the residue dissolved inDMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give thetitle compound as a beige solid (27.5 mg, 36%). HPLC, Rt: 1.86 min(purity: 100%). LC/MS M⁺(ESI): 382.3, M⁻(ESI) 380.3.

Example 117N-[5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-furamide

A sealed vessel containing furan-2-carboxylic acid(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (61 mg, 0.20 mmol, 1mol eq.), cyclopentylamine (26 mg, 0.30 mmol, 1.5 mol eq.),di-iso-propylethylamine (60 μL, 0.32 mmol, 1.6 mol eq.) and n-butanol(0.75 ml) was irradiated at 220° C., with stirring, for 20 minutes. Thesolvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL)and purified by reverse phase preparatory HPLC to give the titlecompound as a white solid (28.4 mg, 46%). HPLC, Rt: 2.32 min (purity:97%). LC/MS M⁺(ESI): 312.3.

Example 118N-[7-chloro-5-(cyclobutylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure described forexample 84, but starting fromN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10),100 mg; 0.32 mmol; 1.0 eq) and cyclobutylamine (139 μL; 1.62 mmol; 5.0eq) heated at 180° C. for 1800 s after which solvents were evaporatedunder vacuum, then resuspended in water, filtered and washed with EtOActo give the title compound as a white solid (23 mg, 21%). HPLC, Rt: 2.95min. (purity 96.7%). LC/MS, M⁺(ESI): 342.8, M⁻(ESI): 340.9.

Example 119N-[7-chloro-5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10),100 mg; 0.32 mmol; 1.0 eq) and cyclopentylamine (161 μL; 1.62 mmol; 5.0eq) to give the title compound as a white solid (5 mg, 4%). HPLC, Rt:3.20 min. (purity 92.3%). LC/MS, M⁺(ESI): 356.9, M⁻(ESI): 354.9.

Example 120N-[7-chloro-5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10),100 mg; 0.32 mmol; 1.0 eq) and cyclohexylamine (187 μL; 1.62 mmol; 5.0eq) to give the title compound as a white solid (26 mg, 22%). HPLC, Rt:3.48 min. (purity 98.5%). LC/MS, M⁺(ESI): 370.9, M⁻(ESI): 368.9.

Example 121N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10),100 mg; 0.32 mmol; 1.0 eq) and sec-butylamine (118 mg; 1.62 mmol; 5.0eq) to give the title compound as a white solid (15 mg, 13%). HPLC, Rt:3.07 min. (purity 96.3%). LC/MS, M⁺(ESI): 344.8, M⁻(ESI): 342.9.

Example 122N-[7-chloro-5-(cyclopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10),100 mg; 0.32 mmol; 1.0 eq) and cyclopropylamine (113 μL; 1.62 mmol; 5.00eq) to give the title compound as a white solid (50 mg, 43%). HPLC, Rt:2.59 min. (purity 92.6%). LC/MS, M⁺(ESI): 328.8, M⁻(ESI): 326.9.

Example 123N-[5-[(2-methoxyethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq) and 2-methoxyethylamine (55.0 mg; 0.73mmol; 5.0 eq), heated at 120° C., to give the title compound as a whitesolid (23 mg, 40%). HPLC, Rt: 2.70 min. (purity 98.1%). LC/MS, M⁺(ESI):380.8, M⁻(ESI): 378.9.

Example 124N-[5-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-amino-1-propanol (56 μL; 0.73mmol; 5.0 eq), heated at 120° C., to give the title compound as anoff-white solid (22 mg, 40%). HPLC, Rt: 2.05 min. (purity 96.2%). LC/MS,M⁺(ESI): 380.8, M⁻(ESI): 378.9.

Example 125N-[5-[(2-hydroxyethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq) and ethanolamine (44 μL; 0.73 mmol; 5.0eq), heated at 120° C., to give the title compound as a white solid (15mg, 28%). HPLC, Rt: 1.91 min. (purity 97.9%). LC/MS, M⁺(ESI): 366.8,M⁻(ESI): 364.9.

Example 126N-[5-(dimethylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq) and dimethylamine (43.0 μL; 0.73 mmol;5.0 eq), heated at 120° C., to give the title compound as a white solid(20 mg, 39%). HPLC, Rt: 2.52 min. (purity 99.7%). LC/MS, M⁺(ESI): 350.8,M⁻(ESI): 348.9.

Example 127N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamideStep a) Formation of pyridin-3-ylacetyl chloride

Oxalyl chloride (211 μl; 2.23 mmol; 1.2 eq.) was added to a suspensionof 3-pyridineacetic acid (255 mg; 1.86 mmol; 1.0 eq.) in DCM/DMF (5 mL:3μL) maintained at 0° C. under nitrogen atmosphere. The reaction mixturewas then stirred at rt for 1 h. It was then concentrated under reducedpressure. The solid obtained was used as such in amidation reactions.

Step b) Formation ofN-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamide

A mixture of pyridin-3-ylacetyl chloride (120.07 mg; 0.77 mmol; 1.50eq.) and N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9);119 mg; 0.51 mmol; 1.0 eq.) in DCM (1 mL) in presence of pyridine (124μL; 1.54 mmol; 3 eq.) was heated in a sealed tube at 55° C. for 3 h.Et₂O and Water were then added to the mixture, the precipitate obtainedwas filtered, washed with water, Et₂O, Acetonitrile and dried undervacuum at 40° C. to give the title compound as an off-white powder (74mg, 41%). HPLC, Rt: 2.49 min. (purity 98.0%). LC/MS, M⁺(ESI): 350.9,M⁻(ESI): 348.9.

Example 128N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperidin-1-ylmethyl)benzamide

To a reaction vessel containingN-5-cyclohexyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine (69 mg, 0.3mmol, 1 eq.) and triethylamine (104 μL, 0.75 mmol, 2.5 eq.) inacetonitrile (1 mL) was added 4-piperidin-1-ylmethyl-benzoyl chloride(178 mg, 0.75 mmol, 2.5 eq) as a solution in acetonitrile (2 mL),dropwise. The vessel was capped and stirred at room temperature forapproximately 16 hours. The solvent was removed in vacuo and theresulting solid dissolved in methanolic ammonia (4 mL, 7 N) and stirredat room temperature for a further 16 hours. The solvent was removed invacuo and the residue dissolved in DMSO (1.5 mL) and purified by reversephase preparatory HPLC to give the title compound as a beige solid (15.3mg, 12%). Rt: 3.86 min (purity: 97%). LC/MS M⁺(ESI): 433.2, M⁻(ESI)431.2.

Example 129N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(pyrrolidin-1-ylmethyl)benzamide

To a reaction vessel containingN-5-cyclohexyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine (69 mg, 0.3mmol, 1 eq.) and pyridine (63 μL, 1.2 mmol, 4 eq.) in dichloromethane (1mL) was added 4-(pyrrolidin-1-ylmethyl)benzoyl chloride hydrochloride(142 mg, 0.6 mmol, 2 eq., prepared from 4-pyrrolidin-1-ylmethyl-benzoicacid, catalytic DMF and oxalyl chloride in DCM) as a solution indichloromethane (2 mL), dropwise. The vessel was capped and heated toreflux for approximately 16 hours. The reaction mixture was cooled andthe solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) andpurified by reverse phase preparatory HPLC to give the title compound asa beige solid (12.4 mg, 10%). HPLC, Rt: 3.50 min (purity: 100%). LC/MSM⁺(ESI): 419.2, M⁻(ESI) 417.2.

Example 130N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}benzamide

To a reaction vessel containing4-chloromethyl-N-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide((B8), 90 mg, 0.23 mmol, 1 eq.) and N,N-diiospropylethylamine (0.35mmol, 61 μL, 1.5 eq.) in dioxane (3 mL) was addedN-(2-methoxyethyl)methylamine (0.28 mmol, 25 μL, 1.2 eq.) dropwise. Thevessel was capped and the reaction stirred at room temperature for 1hour and heated to 80° C. for a further 15 hours. The solvent wasremoved in vacuo and the residue dissolved in DMSO (1.5 mL) and purifiedby reverse phase preparatory HPLC to give the title compound as a lightyellow solid (3.9 mg, 4%). HPLC, Rt: 3.46 min (purity: 93%). LC/MSM⁺(ESI): 437.2, M⁻(ESI) 435.2.

Example 131N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide

This was prepared using the same method as that described forN-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4-(2-oxo-pyrrolidin-1-ylmethyl)-benzamideto giveN-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-methyl-nicotinamideas a brown/yellow solid (36.5 mg, 35%). HPLC, Rt: 3.21 min (purity:95%). LC/MS M⁺(ESI): 351.1, M⁻(ESI) 349.1.

Example 132N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide

To a biotage initiator microwave vial (0.2-0.5 mL) containing6-chloro-N-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-nicotinamide((B11), 0.27 mmol, 100 mg, 1 eq.), 3-aminopropan-1-ol (0.54 mmol, 0.028mL, 2 eq.) and N,N-diiospropylethylamine (0.54 mmol, 0.094 mL, 2 eq.) inbutanol (2 mL), was capped and heated in a biotage initiator 60microwave for 30 minutes at 180° C., and a further 10 minutes at 210° C.The solvent was removed in vacuo and the residue dissolved in DMSO (1.5mL) and purified by reverse phase preparatory HPLC to give the titlecompound as a white solid (33.4 mg, 30%). HPLC, Rt: 2.37 min (purity:92%). LC/MS M⁺(ESI): 410.2, M⁻(ESI) 408.2.

Example 133N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(2-furylmethyl)amino]nicotinamide

The title compound was prepared following the procedure described forthe example 132 but starting from 2-aminomethylfuran as a brown solid(17.5 mg, 15%). HPLC, Rt: 3.50 min (purity: 91%). LC/MS M⁺(ESI): 432.2,M⁻(ESI) 430.2.

Example 134N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide1-oxide Step a) Formation nicotinoyl chloride 1-oxide

The title compound was prepared following procedure described forexample 127, step a), but starting from nicotinic acid N-oxide (255 mg;1.83 mmol; 1.0 eq.). The solid obtained was used as such in amidationreactions.

Step b) Formation ofN-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide1-oxide

A mixture of N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine((A9), 108.00 mg; 0.47 mmol; 1.00 eq.) and nicotinoyl chloride 1-oxide(125 mg; 0.79 mmol; 1.7 eq.) in DCM (1 mL) in the presence of pyridine(113 μL; 1.40 mmol; 3 eq.) was heated in a sealed tube at 55° C. for 3h. Water was then added and the reaction mixture was extracted with DCM(three times). Combined organic phases were then washed with brine,dried over magnesium sulfate, filtrated and con concentrated. The crudewas purified by Mass Directed AutoPrep. The title compound was obtainedafter lyophilisation as a white powder (36 mg, 22%). HPLC, Rt: 2.64 min.(purity 99.4%). LC/MS, M⁺(ESI): 353.0, M⁻(ESI): 351.0.

Example 135N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamidetrihydrochloride

A mixture ofN⁵-isopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine((A17), 73 mg; 0.28 mmol; 1.0 eq.), pyridin-3-ylacetyl chloride (90 mg;0.58 mmol; 2.05 eq.) and Pyridine (67.98 μL) in DCM (1.00 mL) was heatedat 55° C. for 3 h in a sealed tube. Water was added and the reactionmixture was extracted with DCM/MeOH (3:1, three times). Combined organicphases were then washed with brine, dried over magnesium sulfate,filtered and concentrated to give 105 mg of a yellowish powder. Thiscrude was dissolved in MeOH (5 mL) and Et₂O/HCl (9 mL of a 1 M solution)was added. The solution was concentrated under reduced pressure. Aprecipitate was then obtained by addition of DCM/Et₂O (1:1). It wasfiltered and dried under reduced pressure at 40° C. to give the titlecompound as an off-white solid (73 mg, 2%).

HPLC, Rt: 2.94 min. (purity 95.6%). LC/MS, M⁺(ESI): 379.0, M⁻(ESI):377.0. CHN analysis: [C₁₇H₁₇N₆OF₃-3.0 HCl—H₂O] Corrected: C, 40.37%; H,4.38%; N, 16.62%. Found: C, 40.52%; H, 4.28%; N, 16.71%.

Example 136N-[5-[(1-ethylpropyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-aminopentane (86 μL; 0.73 mmol;5.0 eq), heated at 120° C., to give the title compound as a white solid(23 mg, 40%). HPLC, Rt: 3.66 min. (purity 96%). LC/MS, M⁺(ESI): 392.9,M⁻(ESI): 391.0.

Example 137N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide1-oxide

A mixture of nicotinoyl chloride 1-oxide (180.0 mg; 1.12 mmol; 3.4 eq.)andN⁵-isopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine((A17), 86.0 mg; 0.33 mmol; 1.0 eq.) in DCM (1 mL) in presence ofpyridine (80 μL; 1.0 mmol; 3 eq.) was heated in a sealed tube at 55° C.for 3 h. Water was then added to the mixture and the precipitateobtained was filtered, washed with water and DCM and purified by MassDirected AutoPrep. The title compound was obtained after lyophilisationas a white powder (19 mg, 15%). HPLC, Rt: 3.13 min. (purity 99.4%).LC/MS, M⁺(ESI): 380.9, M⁻(ESI): 379.0.

Example 138N-[5-[(3-hydroxycyclohexyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamideformic acid

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide((B7), 50.0 mg; 0.14 mmol; 1.00 eq) and 3-aminocyclohexanol (Betapharma,84 mg; 0.73 mmol; 5.00 eq), heated at 120° C. HCl (1.5 M) in MeOH (2 mL)was added to the solid residue and the salt was precipitated by additionof Et₂O, filtered and dried under vacuum, purified by Mass DirectedAutoPrep and lyophilized to give the title compound as a mixture ofcis:trans isomers as a white solid (11 mg, 18%). HPLC, Rt: 1.72 min.(purity 48.9%, isomer A), 1.87 min. (purity 46.6%, isomer B). LC/MS,M⁺(ESI): 420.9, M⁻(ESI): 418.9.

Example 139N-{7-chloro-5-[(3-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamideformic acid

The title compound was prepared following procedure and work updescribed for example 118, but starting fromN-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10),100 mg; 0.32 mmol; 1.0 eq) and 3-aminocyclohexanol (Betapharma, 187 mg;1.62 mmol; 5.0 eq), heated at 120° C., filtered and dried under vacuum,purified by Mass Directed AutoPrep and lyophilized to give the titlecompound as a mixture of cis:trans isomers as a beige powder (9 mg, 7%).HPLC, Rt: 2.15 min. (purity 57.4%, isomer A), 2.28 min. (purity 34.7%,isomer B). LC/MS, M⁺(ESI): 386.9, M⁻(ESI): 384.9.

Example 140N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(dimethylamino)methyl]benzamide

To a reaction vessel containingN⁵-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine((A18), 77 mg, 0.3 mmol, 1 eq.) and pyridine (0.063 mL, 1.2 mmol, 4 eq.)in dichloromethane (1 mL) was added 4-dimethylaminomethyl-benzoylchloride (118 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2mL), dropwise. The vessel was capped and heated to reflux forapproximately 16 hours. The reaction mixture was cooled and the solventremoved in vacuo. The residue dissolved in DMSO (1.5 mL) and purified byreverse phase preparatory HPLC to give the title compound as a whitesolid (65.1 mg, 52%). HPLC, Rt: 2.59 min (purity: 100%). LC/MS M⁺(ESI):419.2, M⁻(ESI) 417.2.

Example 141N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide

The title compound was prepared following procedure and work updescribed for example 140 but starting from4-[(2-oxopyrrolidin-1-yl)methyl]benzoyl chloride (prepared in DCM from4-[(2-oxopyrrolidin-1-yl)methyl]benzoic acid (Enamine), oxalyl chlorideand catalytic amount of DMF following the procedure described forexample 127, step a)). The title compound was obtained as an off-whitesolid (73.6 mg, 27%). HPLC, Rt: 2.43 min (purity: 94%). LC/MS M⁺(ESI):459.2, M⁻(ESI) 457.2.

Example 142N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-pyrrolidin-1-ylnicotinamide

The title compound was prepared following procedure and work updescribed for example 140 but starting from6-pyrrolidin-1-ylpyridine-3-carbonyl chloride (prepared in DCM from6-(1-pyrrolidinyl)nicotinic acid (ABCR), oxalyl chloride and catalyticamount of DMF following the procedure described for example 127, stepa)). The title compound was obtained as a beige solid (18.5 mg, 14%).HPLC, Rt: 2.70 min (purity: 97%). LC/MS M⁺(ESI): 432.2, M⁻(ESI) 430.2.

Example 143N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide

The title compound was prepared following procedure and work updescribed for example 140 but starting from 6-methylpyridine-3-carbonylchloride (prepared in DCM from 6-methylnicotinic acid, oxalyl chlorideand catalytic amount of DMF following the procedure described forexample 127, step a)). The title compound was obtained as a cream solid(14.6 mg, 13%). HPLC, Rt: 2.35 min (purity: 97%). LC/MS M⁺(ESI): 377.2,M⁻(ESI) 375.2.

Example 144N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperidin-1-ylmethyl)benzamide

Step a) Formation of6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a reaction vessel containing6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A5), 3.44 g, 16.1 mmol, 1eq.), 4-benzyloxy-3-methoxy boronic acid (5.0 g, 19.3 mmol, 1.2 eq.,Synthonix) and cesium fluoride (7.34 g, 48.3 mmol, 3 eq.) indimethylformamide (60 mL) and water (24 mL) was addedbis-triphenylphosphine palladium dichloride (0.3 g, 0.4 mmol, 3%). Thevessel was purged with nitrogen, capped and heated at 80° C. forapproximately 18 hours. After this time, the crude mixture was filteredthrough celite washing the celite with ethyl acetate and water. Theresulting filtrate was extracted with ethyl acetate (3×150 mL) and thecombined organic layers dried (MgSO₄) and concentrated in vacuo. Theresulting residue was purified by flash column chromatography (ethylacetate: petroleum ether; 1:1) to give the title compound as a brownsolid (4.82 g, 86%). HPLC, Rt: 2.55 min (purity 96%). LC/MS M⁺(ESI):347, M⁻(ESI) 345.

Step b) Formation ofN-(6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4-(piperidin-1-ylmethyl)benzamide

To a reaction vessel containing the6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine(104 mg, 0.3 mmol, 1 equivalent) and pyridine (0.063 mL, 1.2 mmol, 4eq.) in dichloromethane (1 mL) was added 4-piperidin-1-ylmethyl-benzoylchloride (142 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2mL), dropwise. The vessel was capped and heated to reflux forapproximately 16 hours. The reaction mixture was cooled and the solventremoved in vacuo. The residue dissolved in DMSO (1.5 mL) and purified byreverse phase preparatory HPLC to giveN-[6-(4-benzyloxy-3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-piperidin-1-ylmethyl-benzamideas a white solid (14.9 mg, 9%).

Step c) Formation ofN-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperidin-1-ylmethyl)benzamide

N-(6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4-(piperidin-1-ylmethyl)benzamide(14.9 mg, 0.027 mmol) was treated with trifluoroacetic acid (2 mL) andthe reaction mixture was stirred for 1 hour at 75° C. The reactionmixture was cooled and the solvent removed in vacuo. The residuedissolved in DMSO (1.5 mL) and purified by reverse phase preparatoryHPLC to give the title compound as a white solid (1.4 mg, 11%). HPLC,Rt: 2.23 min (purity: 99%). LC/MS M⁺(ESI): 458.2, M⁻(ESI) 456.2.

Example 145N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide

The title compound was prepared following procedure and work updescribed for example 145 but starting from 6-methylpyridine-3-carbonylchloride (prepared in DCM from 6-methylnicotinic acid, oxalyl chlorideand catalytic amount of DMF following the procedure described forexample 127, step a)). The title compound was obtained as a cream solid(5.2 mg, 24%). HPLC, Rt: 1.52 min (purity: 98%). LC/MS M⁺(ESI): 376.1,M⁻(ESI) 374.1.

Example 146N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide

The title compound was prepared following procedure and work updescribed for example 144 but starting from4-[(2-oxopyrrolidin-1-yl)methyl]benzoyl chloride (prepared in DCM from4-[(2-oxopyrrolidin-1-yl)methyl]benzoic acid (Enamine), oxalyl chlorideand catalytic amount of DMF following the procedure described forexample 127, step a)). The title compound was obtained as a white solid(4.1 mg, 28%). HPLC, Rt: 1.68 min (purity: 98%). LC/MS M⁺(ESI): 458.2,M⁻(ESI) 456.2.

Example 1474-[(dimethylamino)methyl]-N-[6-(4-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide

The title compound was prepared following procedure and work updescribed for example 144 but starting from4-dimethylaminomethyl-benzoyl chloride (prepared in DCM from4-[(dimethylamino)methyl]benzoic acid (Enamine), oxalyl chloride andcatalytic amount of DMF following the procedure described for example127, step a)). The title compound was obtained as a white solid (13.7mg, 45%). HPLC, Rt: 1.81 min (purity: 97%). LC/MS M⁺(ESI): 418.2,M⁻(ESI) 416.2.

The following additional compounds (Examples 148-182) of Table 1 havebeen prepared following the above protocols.

TABLE 1 Examples of additional Triazolopyridine compounds HPLC M + Ex-purity Rt H Appear- ample Structure Name (%) (min) (ESI) ance 148

N-[5-{[(1R,2S)-2- (hydroxymethyl)cyclohexyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo [1,5-a]pyridin-2-yl]nicotinamidehydrochloride 91.9 3.5 435 white powder 149

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-hydroxy- piperidin-1-yl)methyl]benzamide 93.6 2.4475 pale yellow solid 150

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(pyrrolidin-1- ylmethyl)benzamide 90.2 2.44 445 yellowsolid 151

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(4-hydroxy- piperidin-1-yl)nicotinamide 99 2.85 462off- white solid 152

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-piperazin-1- ylnicotinamide 90.1 2.4 447 yellow solid153

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6- (dimethylamino)nicotinamide 95.9 2.8 406 pale yellowsolid 154

N-[6-bromo-5- (cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide 93 3.6 486 whitesolid 155

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4- ylnicotinamide 98 3.41 448 white solid156

N-[5- (cyclohexylamino)[1,2,4]triazolo[1,5- a]pyridin-2-yl]-6-(dimethylamino)nicotinamide 96.4 2.65 380 off- white solid 157

tert-butyl 4-[5-({[5-(cyclopropyl- amino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino} carbonyl)pyridin-2-yl]piperazine-1-carboxylate 98.8 4 547 brown solid 158

N-[5- (cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-hydroxy- piperidin-1-yl)methyl]benzamide 93.4 2.35449 yellow oil 159

N-[5- (cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(4-fluoropiperidin- 1-yl)nicotinamide 94.7 3.47 438white solid 160

N-[5- (cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(1H-pyrazol-1- yl)nicotinamide 95.7 3.68 403 brownsolid 161

tert-butyl 4-[5-({[5- (cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl) pyridin-2-yl]piperazine-1-carboxylate95.4 3.85 521 off- white solid 162

N-[5-(cyclopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3- hydroxypropyl)amino]nicotinamide 98.5 2.47 436white solid 163

N-[5-(isopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4- ylmethyl)nicotinamide 97.7 3.00 463 off-white solid 164

N-[5-[(pyrrolidin-3-ylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5- a]pyridin-2-yl]nicotinamide 80.82.26 406 yellow solid 165

N-[5- (cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperazin-1- ylmethyl)benzamide 90.8 2.17 434 yellowoil 166

N-[5- (cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-formylpiperazin- 1-yl)methyl]benzamide 86.3 2.24462 yellow oil 167

N-[5-(piperidin-3-ylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide 92.2 2.37 406 yellow oil 168

N-[5-(sec-butylamino)-7- chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(2- methoxyethyl)(methyl)amino] nicotinamide 96.6 3.16 432white solid 169

N-[5-(sec-butylamino)-7- chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino] nicotinamide 98.7 2.49 418 white solid170

N-[5-(sec-butylamino)-7- chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide 98.2 3.5 430 white solid 171

N-[5-(sec-butylamino)-7- chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-{[(2- methoxyethyl)(methyl)amino]methyl} benzamide 96.1 2.27 446yellow solid 172

N-[5-(sec-butylamino)-7- chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide 93 3.14 359 pale brown solid 173

N-[7-chloro-5- (isopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide 98.1 2.99 331 white solid 174

N-[5-[(3-isopropoxyphenyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5- a]pyridin-2-yl]nicotinamide 963.86 457 white solid 175

N-[5-[(3-fluoro-4-methoxyphenyl) amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl] nicotinamide 98.4 3.43 447 yellow solid 176

N-[5-{[3-(benzyloxy)phenyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5- a]pyridin-2-yl]nicotinamide 98.34.02 505 yellow solid 177

N-[5-(sec-butylamino)-7- chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(morpholin-4-ylmethyl) benzamide 93 2.46 443 white solid 178

N-[5-(isopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide 92 3.11 379 pale brown solid 179

6-chloro-N-[5-(isopropylamino)-7- (trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide 99.2 3.69 399 white solid 180

6-[(2-aminoethyl)amino]-N-[5- (isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5- a]pyridin-2-yl]nicotinamide 96.32.37 423 yellow solid 181

N-[5-(sec-butylamino)-7- methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide 84.5 2.47 325 off- white powder 182

N-[5-(isopropylamino)-7- methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide 67 2.15 311 off- white powder

Assays Example 183 Enzyme Inhibition Assays (In Vitro ASK1 Assays)

Assays were performed in a 384 well plate (Corning, #3654) format, usingthe human recombinant ASK1 as an enzyme and MBP (myelin basic protein,Upstate/Millipore, #13-104) with ATP as substrates. Assay read out wasthe measurement of the amount of ATP remaining after stopping thereaction, using a luciferase-based kit from Cambrex.

Materials and Methods

Compounds to be tested were dissolved in 100% DMSO at a concentration of10 mM. Subsequent dilutions were performed in 100% DMSO using a BiomekFX Workstation. 5 μL of diluted compound or vehicle (6% DMSO) wasdistributed to a 384 well plate. 5 μL of substrates (ATP 7.5 μM, MBP 450ng/4) diluted in ASK1 buffer (20 mM Tris HCl pH 7.4, 0.001% Brij35,0.01% BSA, 5 mM MgCl₂, 1 mM DL-Dithiothreitol) were added, followed by 5μL of human recombinant ASK1 enzyme (22.5 ng/mL) diluted in ASK1 bufferin order to start the reaction. The reaction ran for 180 minutes at 30°C. before the addition of 5 μL of stop solution (Cambrex, #LT23-231). 10μL of Pklight ATP detection reagent (Cambrex #LT23-233) were added.After 120 min of incubation, luminescence was measured on a Perkin-ElmerVictor 2 spectrofluorimeter. The percentage of inhibition relative tothe fluorescence observed in the presence of solvent (1% DMSO) alone wasdetermined. The IC₅₀ values for inhibition were determined intriplicates on at least 2 separate occasions.

The results are expressed in terms of IC₅₀ (the concentration ofcompound required to give a 50% decrease in enzyme activity) and arepresented in Table 2 below for compounds of Formula (I).

TABLE 2 IC₅₀ on ASK1 in nM Example No. IC₅₀ (nM) 2  700 ± 200 3 8000 ±400 5 17000 ± 5000 7  7000 ± 1000 10 16000 ± 4000 12 14800 ± 200  301100 ± 500 44 6900 ± 50  45 3380 50  8000 ± 1000 52 1700 ± 200 56 990 ±40 61 180 ± 20 63 9860 66 260 ± 10 72 4080 74 120 ± 10 81 1660 ± 50  831900 ± 200 86 110 ± 50 87 5960 89 460 ± 50 90  700 ± 100 94 5900 96  990± 110 99 42 ± 7 100 56 ± 8 115  519 ± 113 118 87 ± 6 120  67 ± 12 124197 ± 6  130 531 ± 18 132  91 ± 26 140 1140 144 2000 146 138 ± 30 1475500 169 119 ± 29

Example 184 Lipopolysaccharide (LPS)-Induced TNFα Release Assay in Mice

Rationale

The administration of LPS induces the release of TNFα from white bloodcells (monocytes, macrophages, Kupffer cells, etc.) and endothelialcells into the blood. This is a model for cytokine release that occursduring inflammation. Free radical scavengers (Edaravone,N-Acetylcystein, etc) were shown to reduce LPS-induced TNFα release inmice. ASK1 mediates free radical pathways. Based on this mechanism, theblockade of ASK1 by specific inhibitors should reduce LPS-induced TNFαrelease in mice.

Method

Female C3H mice (Elevage Janvier) (8 week old), received E. Coli's LPS(O111:B4, Sigma, 0.3 mg/kg, ip) after the administration of the testarticles. Ninety min later, the animals were sacrificed and the bloodwas sampled. Plasma levels of TNFα were determined in serum using anELISA kit (R&D). LPS was solubilized in sterile saline.

Protocol

The test articles were suspended in 0.5% CMC/0.25% Tween 20 andadministered 15 min prior the challenge of LPS by oral route at thedoses of 3 to 30 mg/kg. Control animals received the vehicle. In timecourse experiments, the test articles were administered 15 min to 4 hrsprior the challenge of LPS. Dexamethasone (0.1 mg/kg, po) was used asreference.

Summary of the Experimental Design

The animals were divided into 5 groups (6 mice each group):

Group 1: (control LPS) received 0.5% CMC/0.25% tween-20 and injection ofLPS;

Group 2: Experimental group (Compound of the invention Dose 1 is 3mg/kg) received a compound of the invention and injection of LPS;

Group 3: Experimental group (Compound of the invention Dose 2 is 10mg/kg) received a compound of the invention and injection of LPS;

Group 4: Experimental group (Compound of the invention Dose 3 is 30mg/kg) received a compound of the invention and injection of LPS;

Group 5: Reference group received the reference compound (dexamethasone)and injection of LPS.

Calculation Inhibition of TNFα Release was Calculated as Follows:

% inhibition=100*(1−(TNFαX)/TNFα 1))

Where TNFα1=TNFα concentration in group 1 (pg/ml), TNFα X=TNFαconcentration in group X (pg/ml).

TABLE 3 Percentage of inhibition of LPS-induced TNFα release in mice bycompounds of the invention: Example Dose (mg/kg) Route % inhibitionExample 2 30 po 49 ± 8 Example 30 30 po 43 ± 3

Formulations Preparation of a Pharmaceutical Formulation Formulation1—Tablets

A compound of Formula (I) is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 240-270 mgtablets (80-90 mg of active compound according to the invention pertablet) in a tablet press.

Formulation 2—Capsules

A compound of Formula (I) is admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active compound according to the inventionper capsule).

Formulation 3—Liquid

A compound of Formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixedwith a previously prepared solution of microcrystalline cellulose andsodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate(10 mg), flavor, and color are diluted with water and added withstirring. Sufficient water is then added to produce a total volume of 5ml.

Formulation 4—Tablets

A compound of Formula (I) is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 450-900 mgtablets (150-300 mg of active compound according to the invention) in atablet press.

Formulation 5—Injection

A compound of Formula (I) is dissolved in a buffered sterile salineinjectable aqueous medium to a concentration of approximately 5 mg/ml.

1. A triazolopyridine compound of formula I:

Formula (I) wherein: R₁ is selected from: a) —NR₆R₇; b)C₃-C₈-cycloalkoxy, or C₁-C₆-alkoxy; c) C₃-C₈-cycloalkyl sulfanyl, orC₁-C₆-alkyl sulfanyl; or d) 5 or 6-membered heteroaryl having at leastone heteroatom selected from N, S or O, said heteroaryl beingsubstituted with C₁-C₆ alkyl, halogen, or C₁-C₆ alkoxy; R₂ is selectedfrom: a) hydrogen; b) halogen; c) aryl that is unsubstituted or issubstituted with R₁₀, R₁₁ and/or R₁₂; or d) 5 to 10-membered heteroarylhaving at least one heteroatom selected from N, S or O and wherein said5 to 10-membered heteroaryl is unsubstituted or is substituted withC₁-C₆ alkyl; or R₁ and R₂ taken together form a —C═C—C═C— group-; R₃ isselected from: a) hydrogen; b) halogen; or c) C₁-C₆-alkyl that isunsubstituted or is substituted with at least one fluoro; R₄ is selectedfrom: a) hydrogen; or b) 5 or 6-membered heteroaryl having at least oneheteroatom selected from N, S or O; R₅ is selected from: a) C₁-C₆-alkylthat is unsubstituted or is substituted with at least one of thefollowing groups: i) alkoxycarbonyl, ii) C₁-C₆-alkoxy, iii) —NC(O)R′wherein R′ is an aryl that is unsubstituted or is substituted withC₁-C₆-alkyl, or iv) benzyloxy; b) aryl-C₁-C₆-alkyl; c) 5 or 6-memberedheteroaryl-C₁-C₆-alkyl having a heteroatom selected from N, S or O thatis unsubstituted or is substituted with C₁-C₆-alkyl, halogen orC₁-C₆-alkoxy; d) C₃-C₆-cycloalkyl that is substituted with phenyl; e) 3to 8-membered heterocycloalkyl having a heteroatom selected from N, S orO that is substituted with an acyl group; f) aryl that is unsubstitutedor is substituted with at least one of the following groups: i)C₁-C₆-alkyl, ii) halogen, iii) C₁-C₆-alkoxy, iv) perfluoro-C₁-C₆-alkyl,v) at least one C₁-C₆-alkoxy that is unsubstituted or is substitutedwith C₁-C₆-alkoxy carbonyl, vi) phenyl, vii) C₁-C₆-alkyl sulfonyl, viii)—NHC(O)C₁-C₆-alkyl, ix) amino-C₁-C₆-alkyl wherein amino is selected from—NH₂, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two substituentsC₁-C₆-alkyl can be the same or different, and wherein the twosubstituents may form a 3 to 8-membered heterocycloalkyl with the N towhich they are attached and wherein the heterocycloalkyl isunsubstituted or is substituted with C₁-C₆-alkyl or with hydroxy, x)—N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl), xi) 5 to 6-memberedheterocycloalkyl-C₁-C₆-alkyl having a heteroatom selected from N and O,or xii) amido-C₁-C₆-alkyl; g) 5 to 10-membered heteroaryl having atleast one heteroatom selected from N, O or S optionally substituted withhalogen; or h) pyridinyl that is unsubstituted or is substituted with atleast one of the following groups: i) halogen, ii) C₁-C₆-alkyl, iii)amino-C₁-C₆-alkyl wherein amino is selected from —NH₂, —NHC₁-C₆-alkyl or—N(C₁-C₆-alkyl)₂, wherein the two substituents C₁-C₆-alkyl can be thesame or different, and wherein the two substituents may form a 3 to8-membered heterocycloalkyl with the N to which they are attached andwherein the heterocycloalkyl is unsubstituted or is substituted withC₁-C₆-alkyl or hydroxy, iv) —NH(hydroxy-C₁-C₆-alkyl), v) —NH-(5-memberedheteroaryl-C₁-C₆-alkyl having as heteroatom O), vi) 5 or 6-memberedheterocycloalkyl-C₁-C₆-alkyl having at least one heteroatom selectedfrom O or N, vii) 5 or 6-membered heterocycloalkyl having at least oneheteroatom selected from O or N and that is unsubstituted or issubstituted with hydroxy, —C(O)OR′ wherein R′ is C₁-C₆-alkyl, halogen orC₁-C₆-alkyl, viii) amino, ix) —NH(amino-C₁-C₆-alkyl), or x)—N(C₁-C₆-alkyl)₂; R₆ is selected from: a) C₁-C₆-alkyl that isunsubstituted or is substituted with one or two hydroxy groups; b)phenyl substituted with at least one of the following groups: i)halogen, ii) C₁-C₆-alkyl, or iii) C₁-C₆-alkoxy; c) 5 or 6-memberedheterocycloalkyl having a heteroatom selected from O or N andsubstituted with C₁-C₆-alkyl; d) C₃-C₈-cycloalkyl substituted with R₈;or e) —(CH₂)_(n)R₉ wherein n equals 1, 2 or 3; R₇ is: a) hydrogen; or b)C₁-C₆-alkyl; or R₆ and R₇ can form a 3 to 8-membered heterocycloalkylwith the N to which they are attached and wherein the heterocycloalkylis substituted with C₁-C₆-alkyl; R₈ is selected from: a) hydrogen; b)hydroxy; c) C₁-C₆-alkyl that is unsubstituted or is substituted withhydroxy; d) C(O)O—C₁-C₆-alkyl; or e) —NH₂; R₉ is selected from: a)C₃-C₈-cycloalkyl that is unsubstituted or is substituted with anunsubstituted C₁-C₆-alkyl; b) 5 or 6-membered heterocycloalkyl having aheteroatom selected from N and O and that is unsubstituted or issubstituted with C₁-C₆-alkyl; c) 5 or 6-membered heteroaryl having aheteroatom selected from N and O that is unsubstituted or is and that isunsubstituted or is substituted with C₁-C₆-alkyl; or d) phenyl; and R₁₀,R₁₁ and R₁₂ are each independently selected from: a) hydrogen; b)halogen; c) hydroxy; d) C₁-C₆-alkyl; e) C₁-C₆-alkoxy; f) cyano; g)—C(O)NH(C₁-C₆-alkyl)amino wherein the amino is —N(CH₃)₂); or h) —NH₂. 2.The triazolopyridine compound according to claim 1 wherein: R₁ isselected from: a) —NR₆R₇; b) C₃-C₈-cycloalkoxy; c) C₃-C₈-cycloalkylsulfanyl; or d) 5 or 6-membered heteroaryl having at least oneheteroatom selected from N, S or O that is substituted with C₁-C₆-alkyl;R₂ is selected from: a) hydrogen; b) Cl or Br; c) aryl that isunsubstituted or is substituted with R₁₀, R₁₁ and/or R₁₂; or d) 5, 6 or9-membered heteroaryl having at least one heteroatom selected from N, Sor O and that is unsubstituted or is substituted with C₁-C₆ alkyl; or R₁and R₂ taken together form a —C═C—C═C— group-; R₃ is selected from: a)hydrogen; b) chloro or bromo; c) methyl; or d) CF₃; R₄ is selected from:a) hydrogen; or b) furanyl; R₅ is selected from: a) C₁-C₆-alkyl that isunsubstituted or is substituted with at least one of the followinggroups: i) alkoxycarbonyl, ii) C₁-C₆-alkoxy, iii) —NHC(O)R′ wherein R′is an aryl that is unsubstituted or is substituted with C₁-C₆-alkyl, oriv) benzyloxy; b) aryl-C₁-C₆-alkyl; c) 5 or 6-memberedheteroaryl-C₁-C₆-alkyl having a heteroatom selected from N, S or O thatis unsubstituted or is and that is unsubstituted or is substituted withC₁-C₆-alkyl, halogen or C₁-C₆-alkoxy; d) C₃-C₆ cycloalkyl that issubstituted with phenyl; e) 3 to 8-membered heterocycloalkyl having aheteroatom selected from N, S or O and that is unsubstituted or issubstituted with an acyl group; f) aryl that is unsubstituted or issubstituted with at least one of the following groups: i) C₁-C₆-alkyl,ii) halogen, iii) C₁-C₆-alkoxy, iv) perfluoro-C₁-C₆-alkyl, v) at leastone C₁-C₆-alkoxy that is unsubstituted or is substituted withC₁-C₆-alkoxy carbonyl, vi) phenyl, vii) C₁-C₆-alkyl sulfonyl, viii)—NC(O)C₁-C₆-alkyl, ix) amino-C₁-C₆-alkyl wherein amino is selected from—NH₂, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,N(C₁-C₆-alkyl)(C₁-C₆-alkoxy-C₁-C₆-alkyl), and the two substituentsC₁-C₆-alkyl can be the same or different, and wherein the twosubstituents may form a 3 to 8-membered heterocycloalkyl with the N towhich they are attached and wherein the heterocycloalkyl isunsubstituted or is substituted with C₁-C₆-alkyl or with hydroxy, x)—N(C₁-C₆-alkyl) (C₁-C₆-alkoxy-C₁-C₆-alkyl), xi) 5 to 6-memberedheterocycloalkyl-C₁-C₆-alkyl having a heteroatom selected from N and O,or xii) amido-C₁-C₆-alkyl; g) 5 to 10-membered heteroaryl having atleast one heteroatom selected from N that is unsubstituted or issubstituted with halogen; or h) pyridinyl that is unsubstituted or issubstituted with at least one of the following groups: i) halogen, ii)C₁-C₆-alkyl that is unsubstituted or is substituted with a 5 or6-membered heterocycloalkyl having at least one heteroatom selected fromO or N, iii) 5 or 6-membered heterocycloalkyl having at least oneheteroatom selected from O or N, iv) —NH(hydroxy-C₁-C₆-alkyl), v)—NH-(5-membered heteroaryl-C₁-C₆-alkyl having as heteroatom O), vi) 5 or6-membered heterocycloalkyl-C₁-C₆-alkyl having at least one heteroatomselected from O or N, vii) 5 or 6-membered heterocycloalkyl having atleast one heteroatom selected from O or N and that is unsubstituted oris substituted with hydroxy, —C(O)OR′ wherein R′ is C₁-C₆-alkyl, halogenor C₁-C₆-alkyl, viii) amino, ix) —NH(amino-C₁-C₆-alkyl), or x)—N(C₁-C₆-alkyl)₂; R₆ is selected from: a) C₁-C₆-alkyl that isunsubstituted or is substituted with one or two hydroxy groups, b)phenyl that is unsubstituted or is substituted with at least one of thefollowing groups: i) halogen, ii) C₁-C₆-alkyl, or iii) C₁-C₆-alkoxy; c)5 or 6-membered heterocycloalkyl having a heteroatom selected from O orN and that is unsubstituted or is substituted with C₁-C₆-alkyl; d)C₃-C₈-cycloalkyl that is unsubstituted or is substituted with R₈; or e)—(CH₂)_(n)R₉ wherein n equals 1, 2 or 3; R₇ is: a) hydrogen; or b)C₁-C₆-alkyl; or R₆ and R₇ can form a 3 to 8-membered heterocycloalkylwith the N to which they are attached and wherein the heterocycloalkylis unsubstituted or is substituted with C₁-C₆-alkyl; R₈ is selectedfrom: a) hydrogen; b) hydroxy; c) unsubstituted or substitutedC₁-C₆-alkyl wherein the substituent is hydroxyl; d) C(O)O—C₁-C₆-alkyl;or e) —NH₂; R₉ is selected from: a) C₃-C₈-cycloalkyl that isunsubstituted or is substituted with an unsubstituted C₁-C₆-alkyl; b) 5or 6-membered heterocycloalkyl having a heteroatom selected from N and Othat is unsubstituted or is substituted with C₁-C₆-alkyl; c) 5 or6-membered heteroaryl having a heteroatom selected from N and O that isunsubstituted or is substituted with C₁-C₆-alkyl; or d) phenyl; and R₁₀,R₁₁ and R₁₂ are each independently selected from: a) hydrogen; b) fluoroor bromo; c) hydroxyl; d) C₁-C₆-alkyl; e) C₁-C₆-alkoxy; f) cyano; g)—C(O)NH(C₁-C₆-alkyl)amino wherein the amino is —N(CH₃)₂); or h) —NH₂. 3.A triazolopyridine compound of the following Formula I-6:

Formula I-6 wherein: R₄ is furanyl; and R₅ is selected fromunsubstituted phenyl; or 5 or 6-membered heteroaryl having a heteroatomselected from N, S or O.
 4. The triazolopyridine compound according toclaim 3, wherein R₅ is a 5-membered heteroaryl having a heteroatomselected from N, S or O.
 5. The triazolopyridine compound according toclaim 3, wherein R₅ is an unsubstituted phenyl.
 6. A triazolopyridinecompound selected from:N-[5-(cyclopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-(5-pyrrolidin-1-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;N-[1,2,4]triazolo[1,5-a]quinolin-2-ylnicotinamide;N-[5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;N-{5-[(3-methoxypropyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-{5-[(2-furylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-{5-[(tetrahydrofuran-2-ylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;N-(5-{[1-(hydroxymethyl)propyl]amino}[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;N-{5-[(2-methoxyethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-{5-[(2,3-dihydroxypropyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-[5-(benzylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamidedihydrochloride;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-(5-{[(5-methyl-2-furyl)methyl]amino}[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;N-{5-[(tetrahydrofuran-2-ylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-[5-(cyclooctylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-{5-[cyclohexyl(methyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-[5-(tetrahydro-2H-pyran-4-ylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-{5-[(1-methylpiperidin-4-yl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-{5-[(3-aminocyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-{5-[(1-methylpiperidin-4-yl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}benzamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclohexylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cycloheptylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclopentylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-[(cyclohexylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-{5-[(3-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-{5-[(4-tert-butylcyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-[5-(tetrahydro-2H-pyran-3-ylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(morpholin-4-ylmethyl)benzamide;N-[5-(cyclohexylthio)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-{5-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-[5-(cyclobutylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(dimethylamino)methyl]benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-(morpholin-4-ylmethyl)benzamide;N-[5-[(cyclopropylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;methyltrans-4-{[2-[(pyridin-3-ylcarbonyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-5-yl]amino}cyclohexanecarboxylate;N-[5-{[(1RS,2RS)-2-(hydroxymethyl)cyclohexyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[6-bromo-5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cycloheptylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide;N-(3-{[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}-3-oxopropyl)benzamide;N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(sec-butylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(methylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-(3-methoxyphenyl)acetamide;N-[5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4-ylmethyl)nicotinamide;N-{5-[(cyclohexylmethyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamide;N-{5-[(4-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-methoxybenzamide;N-[5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-furamide;N-[7-chloro-5-(cyclobutylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[7-chloro-5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[7-chloro-5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[7-chloro-5-(cyclopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-[(2-methoxyethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-[(2-hydroxyethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(dimethylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperidin-1-ylmethyl)benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(pyrrolidin-1-ylmethyl)benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(2-furylmethyl)amino]nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide1-oxide;N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-pyridin-3-ylacetamidetrihydrochloride;N-[5-[(1-ethylpropyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide1-oxide;N-[5-[(3-hydroxycyclohexyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamideformic acid;N-{7-chloro-5-[(3-hydroxycyclohexyl)amino][1,2,4]triazolo[1,5-a]pyridin-2-yl}nicotinamideformic acid;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(dimethylamino)methyl]benzamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-pyrrolidin-1-ylnicotinamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;N-[5-{[(1R,2S)-2-(hydroxymethyl)cyclohexyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamidehydrochloride;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-hydroxypiperidin-1-yl)methyl]benzamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(pyrrolidin-1-ylmethyl)benzamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(4-hydroxypiperidin-1-yl)nicotinamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-piperazin-1-ylnicotinamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(dimethylamino)nicotinamide;N-[6-bromo-5-(cyclopentylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(dimethylamino)nicotinamide;tert-butyl4-[5-({[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)pyridin-2-yl]piperazine-1-carboxylate;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-hydroxypiperidin-1-yl)methyl]benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(4-fluoropiperidin-1-yl)nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(1H-pyrazol-1-yl)nicotinamide;tert-butyl4-[5-({[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}carbonyl)pyridin-2-yl]piperazine-1-carboxylate;N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide;N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-(morpholin-4-ylmethyl)nicotinamide;N-[5-[(pyrrolidin-3-ylmethyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(piperazin-1-ylmethyl)benzamide;N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-[(4-formylpiperazin-1-yl)methyl]benzamide;N-[5-(piperidin-3-ylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(2-methoxyethyl)(methyl)amino]nicotinamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-[(3-hydroxypropyl)amino]nicotinamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-morpholin-4-ylnicotinamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-{[(2-methoxyethyl)(methyl)amino]methyl}benzamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;N-[7-chloro-5-(isopropylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-[(3-isopropoxyphenyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-[(3-fluoro-4-methoxyphenyl)amino]-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-{[3-(benzyloxy)phenyl]amino}-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(sec-butylamino)-7-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-(morpholin-4-ylmethyl)benzamide;N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-6-methylnicotinamide;6-chloro-N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;6-[(2-aminoethyl)amino]-N-[5-(isopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N-[5-(sec-butylamino)-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;orN-[5-(isopropylamino)-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide.7. A triazolopyridine intermediate compound selected from:5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine;5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine;5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine;N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;N⁵-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine;[1,2,4]triazolo[1,5-a]quinolin-2-amine;6-bromo-N⁵-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;N⁵-isopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide;N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;4-(chloromethyl)-N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]benzamide;N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide;6-chloro-N-[5-(cyclohexylamino)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide;N⁵-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine;5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine; orN-(5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide. 8.A pharmaceutical composition containing at least one triazolopyridineamide compound according to claim 1 and a pharmaceutically acceptablecarrier, diluent or excipient.
 9. A pharmaceutical compositioncontaining at least one triazolopyridine amide compound according toclaim 3 and a pharmaceutically acceptable carrier, diluent or excipient.10. A pharmaceutical composition containing at least onetriazolopyridine amide compound according to claim 6 and apharmaceutically acceptable carrier, diluent or excipient.